Use of monomeric insulin as a means for improving the bioavailability of inhaled insulin

ABSTRACT

The need for the delivery of insulin by injection can be reduced or eliminated by a method whereby an aerosolized insulin formulation is delivered to a patient&#39;s lungs and the rate at which the insulin is absorbed into the blood is increased by the use of monomeric insulin and/or an inhale-exhale breathing maneuver. Particles of insulin and in particular monomeric insulin delivered to the surface of lung tissue will be absorbed into the circulatory system. The rate of absorption is enhanced by the monomeric form of insulin and by instructing the patient to inhale maximally and thereafter exhale maximally. This maneuver causes a spike in the rate at which insulin enters the circulatory system thereby increasing the rate at which glucose is removed from the circulatory system. The insulin or insulin analog may be a dry powder but is preferably in a liquid formulation delivered to the patient from a hand-held, self-contained device which automatically releases an aerosolized burst of formulation. The device includes a sensor which is preferably electronic which measures inspiratory flow and volume which measurement can be used to control the point of drug release. The sensor can also assist the patient in the inhale-exhale maneuver.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation-in-part of application Ser. No.08/754,423, filed Nov. 22, 1996 now U.S. Pat. No. 5,473,250 issued Apr.28, 1998 which is a continuation-in-part of earlier filed applicationSer. No. 08/549,343, filed Oct. 27, 1995 which application is acontinuation-in-part of earlier filed application Ser. No. 08/331,056,filed Oct. 28, 1994 now U.S. Pat. No. 5,672,581 issued Sep. 30, 1997which is a continuation-in-part of earlier filed application Ser. No.08/011,281 filed Jan. 29, 1993, now issued U.S. Pat. No. 5,364,838,issued Nov. 15, 1994, each of which is incorporated herein by referenceand to which is claimed priority under 35 USC §120.

FIELD OF THE INVENTION

This invention relates generally to a method of, aerosolized drugdelivery. More specifically, this invention relates to the controlledintrapulmonary delivery of a monomeric insulin analog alone or incombination with other treatment methodologies which are combined tosignificantly reduce or eliminate the need for administering insulin byinjection.

BACKGROUND OF THE INVENTION

Diabetes Mellitus is a disease affecting approximately 7.5 millionpeople in the United States. The underlying cause of this disease isdiminished or absent insulin production by the Islets of Langerhans inthe pancreas. Of the 7.5 million diagnosed diabetics in the UnitedStates, approximately one-third are treated using insulin replacementtherapy. Those patients receiving insulin typically self-administer oneor more doses of the drug per day by subcutaneous injection. Insulin isa polypeptide with a nominal molecular weight of 6,000 Daltons. Insulinhas traditionally been produced by processing pig and cow pancreas toallow isolation of the natural product. More recently, recombinanttechnology has made it possible to produce human insulin in vitro. It isthe currently common practice in the United States to institute the useof recombinant human insulin in all of those patients beginning insulintherapy.

It is known that most proteins are rapidly degraded in the acidicenvironment of the GI tract. Since insulin is a protein which is readilydegraded in the GI tract, those in need of the administration of insulinadminister the drug by subcutaneous injection (SC). No satisfactorymethod of orally administering insulin has been developed. The lack ofsuch an oral delivery formulation for insulin creates a problem in thatthe administration of drugs by injection can be both psychologically andphysically painful.

In an effort to provide for a non-invasive means for administeringinsulin, and thereby eliminate the need for hypodermic syringes,aerosolized insulin formulations have been theorized. Aerosolizedinsulin formulations have been shown to produce insulin blood levels inman when these aerosols are introduced onto nasal or pulmonary membrane.Moses et al. Diabetes, Vol. 32, November 1983! demonstrated that ahypoglycemic response could be produced following nasal administrationof 0.5 units/kg. Significant inter-subject variability was noted, andthe nasal insulin formulation included unconjugated bile salts topromote nasal membrane penetration of the drug. Salzman et al. NewEngland Journal of Medicine, Vol. 312, No. 17! demonstrated that anintranasal aerosolized insulin formulation containing a non-ionicdetergent membrane penetration enhancer was effective in producing ahypoglycemic response in diabetic volunteers. Their work demonstratedthat nasal irritation was present in varying degrees among the patientsstudied. In that diabetes is a chronic disease which must becontinuously treated by the administration of insulin and in thatmucosal irritation tends to increase with repeated exposures to themembrane penetration enhancers, efforts at developing a non-invasivemeans of administering insulin via nasal administration have not beencommercialized.

In 1971, Wigley et al. Diabetes, Vol 20, No. 8! demonstrated that ahypoglycemic response could be observed in patients inhaling an aqueousformulation of insulin into the lung. Radio-immuno assay techniquesdemonstrated that approximately 10 percent of the inhaled insulin wasrecovered in the blood of the subjects. Because the surface area ofmembranes available to absorb insulin is much greater in the lung thanin the nose, no membrane penetration enhancers are required for deliveryof insulin to the lungs by inhalation. The inefficiency of delivery seenby Wigley was greatly improved in 1979 by Yoshida et al. Journal ofPharmaceutical Sciences, Vol. 68, No. 5! who showed that almost 40percent of insulin delivered directly into the trachea of rabbits wasabsorbed into the bloodstream via the respiratory tract. Both Wigley andYoshida showed that insulin delivered by inhalation could be seen in thebloodstream for two or more hours following inhalation.

Aerosolized insulin therefore can be effectively given if the aerosol isappropriately delivered into the lung. In a review article, DieterKohler Lung, supplement pp. 677-684! remarked in 1990 that multiplestudies have shown that aerosolized insulin can be delivered into andabsorbed from the lung with an expected absorption half-life of 15-25minutes. However, he comments that "the poor reproducibility of theinhaled dose of insulin! was always the reason for terminating theseexperiments." This is an important point in that the lack of precisereproducibility with respect to the administration of insulin iscritical. The problems associated with the inefficient administration ofinsulin cannot be compensated for by administering excess amounts of thedrug in that the accidental administration of too much insulin could befatal.

Effective use of an appropriate nebulizer can achieve high efficiency indelivering insulin to human subjects. Laube et al. Journal of AerosolMedicine, Vol. 4, No. 3, 1991! have shown that aerosolized insulindelivered from a jet nebulizer with a mass median aerodynamic diameterof 1.12 microns, inhaled via a holding chamber at a slow inspiratoryflow rate of 17 liters/minute, produced an effective hypoglycemicresponse in test subjects at a dose of 0.2 units/kg. Colthorpe et al.Pharmaceutical Research, Vol. 9, No. 6, 1992! have shown thataerosolized insulin given peripherally into the lung of rabbits producesa bioavailability of over 50 percent in contrast to 5.6 percentbioavailability seen for liquid insulin dripped onto the centralairways. Colthorpe's work supports the contention that aerosolizedinsulin must be delivered peripherally into the lung for maximumefficiency and that inadvertent central deposition of inhaledaerosolized insulin will produce an effect ten times lower than thatdesired. Variations in dosing of 10-fold are clearly unacceptable withrespect to the administration of most drugs, and in particular, withrespect to the administration of insulin.

The present invention endeavors to provide a on-invasive methodology forenhancing the rate and extent of absorption of an aerosolized monomericinsulin analog delivered to a patient.

SUMMARY OF THE INVENTION

Blood glucose levels are rapidly decreased by inhaling a monomericinsulin analog which quickly enters the circulatory system after beinginhaled into the lung. The rapid effect is obtained by substantiallyreducing or eliminating sequestration of drug on the lung tissue afterbeing inhaled. Formulations of monomeric insulin analogs are preferablyaerosolized and administered via hand-held, self-contained units whichare automatically actuated at the same release point in a patient'sinspiratory flow cycle. The release point is automatically determinedeither mechanically or, more preferably calculated by a microprocessorwhich receives data from a sensor making it possible to determineinspiratory flow rate and inspiratory volume. The device can measure,provide information to the patient and as such control the inhale-exhalemaneuver. Preferably the device is loaded with a cassette comprised ofan outer housing which holds a package of individual disposablecollapsible containers of a monomeric insulin analog containingformulation for systemic delivery. Actuation of the device forces theinsulin analog formulation through a porous membrane of the containerwhich membrane has pores having a diameter in the range of about 0.25 to3.0 microns, preferably 0.25 to 1.5 microns. The porous membrane ispositioned in alignment with a surface of a channel through which apatient inhales air. The flow profile of air moving through the channelis such that the flow at the surface of the channel is less than theflow rate at the center of the channel. The membrane is designed so thatit outwardly protrudes at all times or is made flexible so that when aninsulin formulation is forced against and through the membrane theflexible membrane protrudes outward beyond the flow boundary layer ofthe channel into faster moving air. Because the membrane protrudes intothe faster moving air of the channel the particles of aerosol formed areless likely to collide allowing for the formation of a burst of fineaerosol mist with uniform particle size.

The dose of insulin analog to be delivered to the patient varies with anumber of factors--most importantly the patient's blood glucose level.Thus, the device can deliver all or any proportional amount of theformulation present in the container. If only part of the contents areaerosolized the remainder can be aerosolized at a later time.

Smaller particle sizes are preferred to obtain systemic delivery ofinsulin analog. Thus, in one embodiment, after the aerosolized mist isreleased into the channel energy is actively added to the particles inan amount sufficient to evaporate carrier and thereby reduce particlesize. The air drawn into the device can be actively heated by moving theair through a heating material which material is pre-heated prior to thebeginning of a patient's inhalation. The amount of energy added can beadjusted depending on factors such as the desired particle size, theamount of the carrier to be evaporated, the water vapor content of thesurrounding air and the composition of the carrier.

To obtain systemic delivery it is desirable to get the aerosolizedformulation deeply into the lung. This is obtained, in part, byadjusting particle sizes. Particle diameter size is generally about oneto three times the diameter of the pore from which the particle isextruded. In that it is technically difficult to make pores of 2.0microns or less in diameter the use of evaporation can reduce particlesize to 3.0 microns or less even with pore sizes well above 1.5 microns.Energy may be added in an amount sufficient to evaporate all orsubstantially all carrier and thereby provide particles of dry powderedinsulin or highly concentrated insulin formulation to a patient whichparticles are uniform in size regardless of the surrounding humidity andsmaller due to the evaporation of the carrier.

In addition to adjusting particle size, systemic delivery of insulin isobtained by releasing an aerosolized dose at a desired point in apatient's respiratory cycle. When providing systemic delivery it isimportant that the delivery be reproducible.

Reproducible dosing of insulin to the patient is obtained by providingfor automatic release of formulation in response to a determinedinspiratory flow rate and measured inspiratory volume. The methodinvolves measuring for, determining and/or calculating a firing point ordrug release decision based on instantaneously (or real time)calculated, measured and/or determined inspiratory flow rate andinspiratory volume points. To obtain repeatability in dosing theformulation is repeatedly released at the same measured (1) inspiratoryflow rate and (2) inspiratory volume. To maximize the efficiency of thedelivery of the formulation is released at (3) a measured inspiratoryflow rate in the range of from about 0.1 to about 2.0 liters/second and(2) a measured inspiratory volume in the range of about 0.1 to about 1.5liters.

A primary object of the invention is to provide for a method ofincreasing the rate at which glucose levels can be decreased bydelivering a formulation of monomeric insulin analog which is depositedon the lungs and thereafter quickly enters the circulatory system.

Another object is to provide a method of administering a monomericinsulin analog formulation to a patient wherein the formulation isrepeatedly delivered to a patient at the same measured inspiratory flowrate (in the range of 0.1 to 2.0 liters/second) and separatelydetermined inspiratory volume (in the range of 0.15 to 1.5 liters).

Another object of the invention is to combine delivery therapies forinhaling an insulin analog with monitoring technologies so as tomaintain tight control over the serum glucose level of a patientsuffering from diabetes mellitus.

Another object of the invention is to provide a device which allows forthe intrapulmonary delivery of controlled amounts of a monomeric insulinanalog formulation based on the particular needs of the diabetic patientincluding serum glucose levels and insulin sensitivity.

Another object of the invention is to provide a means for treatingdiabetes mellitus which involves supplementing insulin administrationusing an intrapulmonary delivery means in combination with injections ofinsulin and/or oral hypoglycemic agents such as sulfonylureas.

Another advantage of the present invention is that the methodologyallows the administration of smaller doses of insulin by a convenientand painless route, thus decreasing the probability of insulinoverdosing and increasing the probability of safely maintaining desiredserum glucose levels.

Another feature of the device of the present invention is that it may beprogrammed to provide variable dosing so that different doses aredelivered to the patient at different times of the day coordinated withmeals and/or other factors important to maintain proper serum glucoselevels with the particular patient.

Another feature of the invention is that the portable, hand-heldinhalation device of the invention can be used in combination with aportable device for measuring serum glucose levels in order to closelymonitor and titrate dosing based on actual glucose levels.

Yet another feature of the invention is that the microprocessor of thedelivery device can be programmed to prevent overdosing by preventingthe formulation release valve from being opened more than a given numberof times within a given period of time.

An object of the invention is to provide a container which holds anaerosolizable formulation of monomeric insulin analog which containercomprises a porous membrane which protrudes outward in a stationarystate or on the application of force forming a convex surface when drugformulation is forced against and through the membrane.

Another object is to provide a method for creating an aerosol of amonomeric insulin formulation which comprises drawing air over a surfaceof a porous membrane in a channel and forcing formulation against themembrane so as to protrude the membrane through a flow boundary layerinto faster moving air of the channel.

Another object of the invention is to adjust particle size by addingenergy to the particles in an amount sufficient to evaporate carrier andreduce total particle size.

Another object is to provide a drug delivery device which includes adesiccator for drying air in a manner so as to remove water vapor andthereby provide consistent particle sizes even when the surroundinghumidity varies.

Another object is to provide a device for the delivery of aerosols whichmeasures humidity via a solid state hygrometer.

A feature of the invention is that drug can be dispersed or dissolved ina liquid carrier such as water and dispersed to a patient as dry orsubstantially dry particles.

Another advantage is that the size of the particles delivered will beindependent of the surrounding humidity.

Another advantage is that the monomeric insulin analog can be stored ina dry state until just prior to delivery.

These and other objects, advantages and features of the presentinvention will become apparent to those persons skilled in the art uponreading the details of the structure of the device, formulation ofcompositions and methods of use, as more fully set forth below.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is a cross-sectional view of a container of the invention;

FIG. 2 is a cross-sectional view of a preferred embodiment of acontainer of the invention;

FIG. 3 is a cross-sectional view of the container of FIG. 2 in use in achannel of a drug delivery device;

FIG. 4 is a plan view of a drug delivery device of the invention;

FIG. 5 is a graph plotting the density of water vapor in air versustemperature;

FIG. 6 is a graph plotting the density of ethanol vapor in air versustemperature;

FIG. 7 is a perspective view of the package of the invention;

FIG. 8 is a perspective view of a container of the invention;

FIG. 9 is a graph showing data points plotted in four general areas withthe points plotted relative to inspiratory flow rate (on the abscissa)and inspiratory volume (on the ordinate) in two dimensions;

FIG. 10 is a graph showing the four general areas plotted per FIG. 1 nowplotted with a third dimension to show the percentage of drug reachingthe lungs based on a constant amount of drug released;

FIG. 11 is a three dimensional graph showing the therapeutic values forinspiratory flow rate and inspiratory volume which provide better drugdelivery efficiency;

FIG. 12 shows a preferred range of the values shown in FIG. 11;

FIG. 13 shows a particularly preferred range for the valves of FIG. 11;

FIG. 14 is a schematic view of a dual compartment insulin formulationcontainer;

FIG. 15 is a graph plotting the amount of insulin and glucose in plasmaover time;

FIG. 16 is a graph plotting the amount of insulin and glucose in plasmaover time;

FIG. 17 is a graph plotting the amount of insulin and glucose in plasmaover time;

FIG. 18 is a graph plotting the amount of insulin and glucose in plasmaover time; and

FIG. 19 is a graph plotting the amount of insulin and glucose in plasmaover time.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

Before the present method of delivering aerosolized monomeric insulinanalog to treat diabetes mellitus and devices, containers andformulations used in the treatment are described, it is to be understoodthat this invention is not limited to the particular methodology,containers, devices and formulations described, as such methods, devicesand formulations may, of course, vary. It is also to be understood thatthe terminology used herein is for the purpose of describing particularembodiments only, and is not intended to limit the scope of the presentinvention which will be limited only by the appended claims.

It must be noted that as used herein and in the appended claims, thesingular forms "a," "and," and "the" include plural referents unless thecontext clearly dictates otherwise. Thus, for example, reference to "aformulation" includes mixtures of different formulations, reference to"an analog" refers to one or mixtures of insulin analogs, and referenceto "the method of treatment" includes reference to equivalent steps andmethods known to those skilled in the art, and so forth.

Unless defined otherwise, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. Although any methods, devicesand materials similar or equivalent to those described herein can beused in the practice or testing of the invention, the preferred methods,devices and materials are now described. All publications mentionedherein are incorporated herein by reference for the purpose ofdescribing and disclosing devices, formulations and methodologies whichare described in the publication and which might be used in connectionwith the presently described invention.

Definitions

The term "insulin" shall be interpreted to encompass natural extractedhuman insulin, recombinantly produced human insulin, insulin extractedfrom bovine and/or porcine sources, recombinantly produced porcine andbovine insulin and mixtures of any of these insulin products. The termis intended to encompass the polypeptide normally used in the treatmentof diabetics in a substantially purified form but encompasses the use ofthe term in its commercially available pharmaceutical form whichincludes additional excipients. The insulin is preferably recombinantlyproduced and may be dehydrated (completely dried) or in solution.

The terms "insulin analog," "monomeric insulin" and the like are usedinterchangeably herein and are intended to encompass any form of"insulin" as defined above wherein one or more of the amino acids withinthe polypeptide chain has been replaced with an alternative amino acidand/or wherein one or more of the amino acids has been deleted orwherein one or more additional amino acids has been added to thepolypeptide chain or amino acid sequences which act as insulin indecreasing blood glucose levels. In general, the "insulin analogs" ofthe present invention include "insulin lispro" as disclosed in U.S. Pat.No. 5,547,929, issued Aug. 20, 1996 (incorporated herein by reference)and analogs referred to as "super insulin analogs" wherein the abilityof the insulin analog to affect serum glucose levels is substantiallyenhanced as compared with conventional insulin as well ashepatoselective insulin analogs which are more active in the liver thanin adipose tissue. Preferred analogs are monomeric insulin analogs whichare insulin-like compounds used for the same general purpose as insulinsuch as insulin lispro i.e., compounds which are administered to reduceblood glucose levels. Monomeric analogs do not bind into groups ofmolecules such as the hexamers formed by conventional recombinant humaninsulin.

The term "acceptable serum glucose level" is intended to mean a glucoselevel above 50 mg/dl and below 300 mg/dl more preferably 80 mg/dl to 200mg/dl and most preferably about 100 mg/dl. It will be understood bythose skilled in the art that levels of about 50 mg/dl are consideredlow and that levels of about 300 mg/dl are considered high, althoughacceptable in the sense that these levels are generally not fatal. It isan important aspect of the invention to maintain more acceptable levelswhich are above the low of 50 mg/dl and below the high of 300 mg/dl withit being more acceptable to deliver doses of insulin so as to keep thepatient as close as possible to about 100 mg/dl.

The term "dosing event" shall be interpreted to mean the administrationof insulin and/or an insulin analog to a patient in need thereof by theintrapulmonary route of administration which event may encompass one ormore releases of formulation from a dispensing device (from one or morecontainers) over a period of time of 15 minutes or less, preferably 10minutes or less, and more preferably 5 minutes or less, during whichperiod one or more inhalations are made by the patient and one or moredoses of insulin or insulin analog are released and inhaled. A dosingevent shall involve the administration of insulin or insulin analog tothe patient in an amount of about 1 unit to about 30 units in a singledosing event which may involve the release of from about 1 to about 300units of insulin from the device.

The term "measuring" describes an event whereby either or both theinspiratory flow rate and inspiratory volume of the patient is measured.The measurement may be used to judge the extent of any inhale-exhalemaneuver and/or in order to determine an optimal point in theinspiratory cycle at which to release aerosolized formulation. It isalso preferable to continue measuring inspiratory flow during and afterany drug delivery and to record inspiratory flow rate and volume before,during and after the release of drug. Such reading makes it possible todetermine if formulation was properly delivered to the patient. Amicroprocessor or other device can calculate volume based on a measuredflow rate. When either flow rate or volume becomes known in any mannerit can be said to have been determined.

The term "monitoring" event shall mean measuring lung functions such asinspiratory flow, inspiratory flow rate, and/or inspiratory volume sothat a patient's lung function as defined herein, can be evaluatedbefore and/or after drug delivery thereby making it possible to evaluatethe effect, if any, of delivery on the patient's lung function.

The term "inspiratory flow rate" shall mean a value of air flow ratemeasured, calculated and/or determined based on the speed of the airpassing a given point in a measuring device assuming atmosphericpressure ±5% and a temperature in the range of about 10° C. to 40° C.

The term "inspiratory flow" shall be interpreted to mean a value of airflow calculated based on the speed of the air passing a given pointalong with the volume of the air that has passed that point with thevolume calculation being based on integration of the flow rate data andassuming atmospheric pressure, ±5% and temperature in the range of about10° C. to about 40° C.

The term "inspiratory volume" shall mean a determined, calculated and/ormeasured volume of air passing a given point into the lungs of a patientassuming atmospheric pressure ±5% and a temperature in the range of 10°C. to 40° C.

The term "inhaling maximally" shall mean that the patient makes amaximal effort to inhale air into the lungs.

The terms "exhaling the forced vital capacity" and "exhaling maximally"are used interchangeably herein and shall mean making a maximal effortto exhale all air from the lungs, preferably exhaling all air in thelungs but for the residual volume.

The term "inhale-exhale" maneuver shall mean inhaling maximally followedby exhaling maximally. After inhaling maximally the patient can hold theinhaled air for any desired period of time before exhaling maximally orexhale maximally immediately following the maximal inhale.

The term "inspiratory flow profile" shall be interpreted to mean datacalculated in one or more events measuring inspiratory flow andcumulative volume, which profile can be used to determine a point withina patient's inspiratory cycle which is preferred for the release of drugto be delivered to a patient. The point within the inspiratory cyclewhere drug is released may be based on a point within the inspiratorycycle likely to result in the maximum delivery of drug and based and/oron a point in the cycle most likely to result in the delivery of areproducible amount of drug to the patient at each release of drug.Repeatability of the amount delivered is the primary criterion andmaximizing the amount delivered is an important but secondary criterion.Thus, a large number of different drug release points might be selectedand provide for repeatability in dosing provided the selected point isagain selected for subsequent releases. To insure maximum drug deliverythe point is selected within given parameters.

The term "therapeutic index" refers to the therapeutic index of a drugdefined as LD₅₀ /ED₅₀. The LD₅₀ (lethal dose, 50%) is defined as thedose of a drug which kills 50% of the tested animals, and the ED₅₀ isdefined as the effective dose of the drug for 50% of the individualstreated. Drugs with a therapeutic index near unity (i.e. LD₅₀ /ED₅₀ isapproximately equal to 1) achieve their therapeutic effect at doses veryclose to the toxic level and as such have a narrow therapeutic window,i.e. a narrow dose range over which they may be administered.

The term "liquid formulation" is used herein to describe anypharmaceutically active insulin, analog thereof, or other drug fortreating diabetes mellitus by itself or with a pharmaceuticallyacceptable carrier in flowable liquid form and preferably having aviscosity and other characteristics such that the formulation isaerosolized into particles which are inhaled into the lungs of a patientafter the formulation is moved through a porous membrane of theinvention. Such formulations are preferably solutions, e.g. aqueoussolutions, ethanolic solutions, aqueous/ethanolic solutions, salinesolutions and colloidal suspensions. Formulations can be solutions orsuspensions of drug in any fluid including fluids in the form of a lowboiling point propellant.

The term "formulation" is used to encompass the term "liquidformulation" and to further include dry powders of an insulin analogwhich is preferably a monomeric insulin analog with or without excipientmaterials.

The term "substantially" dry shall mean insulin or an analog in acontainer or in particles of an aerosol which contain less than 10% freewater, ethanol or other liquid carrier based on total weight andpreferably contains no detectable free liquid carrier.

The terms "lung function" and "pulmonary function" are usedinterchangeably and shall be interpreted to mean physically measurableoperations of a lung including but not limited to (1) inspiratory and(2) expiratory flow rates as well as (3) lung volume. Methods ofquantitatively determining pulmonary function are used to measure lungfunction. Methods of measuring pulmonary function most commonly employedin clinical practice involve timed measurement of inspiratory andexpiratory maneuvers to measure specific parameters. For example, forcedvital capacity (FVC) measures the total volume in liters exhaled by apatient forcefully from a deep initial inspiration. This parameter, whenevaluated in conjunction with the forced expired volume in one second(FEV₁), allows bronchoconstriction to be quantitatively evaluated. Aproblem with forced vital capacity determination is that the forcedvital capacity maneuver (i.e. forced exhalation from maximum inspirationto maximum expiration) is largely technique dependent. In other words, agiven patient may produce different FVC values during a sequence ofconsecutive FVC maneuvers. The FEF 25-75 or forced expiratory flowdetermined over the mid-portion of a forced exhalation maneuver tends tobe less technique dependent than the FVC. Similarly, the FEV₁ tends tobe less technique dependent than FVC. In addition to measuring volumesof exhaled air as indices of pulmonary function, the flow in liters perminute measured over differing portions of the expiratory cycle can beuseful in determining the status of a patient's pulmonary function. Inparticular, the peak expiratory flow, taken as the highest air flow ratein liters per minute during a forced maximal exhalation, is wellcorrelated with overall pulmonary function in a patient with asthma andother respiratory diseases. The present invention carries out treatmentby administering drug in a drug delivery event and monitoring lungfunction in a monitoring event. A series of such events may be carriedout and repeated over time.

The term "velocity of the drug" or "velocity of particles" shall meanthe average speed of particles of respiratory drug formulation movingfrom a release point such as a porous membrane or a valve to a patient'smouth. In a preferred embodiment the velocity of the particles is zeroor substantially zero in the absence of flow created by patientinhalation.

The term "bulk flow rate" shall mean the average velocity at which airmoves through a channel considering that the flow rate is at a maximumin the center of the channel and at a minimum at the inner surface ofthe channel.

The term "flow boundary layer" shall mean a set of points defining alayer above the inner surface of a channel through which air flowswherein the air flow rate below the boundary layer is substantiallybelow the bulk flow rate, e.g., 50% or less than the bulk flow rate.

The term "carrier" shall mean a liquid, flowable, pharmaceuticallyacceptable excipient material which insulin or insulin analog issuspended in or more preferably dissolved in. Useful carriers do notadversely interact with the insulin analog and have properties whichallow for the formation of aerosolized particles preferably particleshaving a diameter in the range of 0.5 to 3.0 microns when a formulationcomprising the carrier and respiratory drug is forced through poreshaving a diameter of 0.25 to 3.0 microns. Preferred carriers includewater, ethanol and mixtures thereof. Other carriers can be used providedthat they can be formulated to create a suitable aerosol and do notadversely effect insulin, and insulin analog or human lung tissue.

The term "measuring" describes an event whereby either the inspiratoryflow rate or inspiratory volume of the patient is measured in order todetermine an optimal point in the inspiratory cycle at which to releaseaerosolized drug. An actual measurement of both rate and volume may bemade or the rate can be directly measured and the volume calculatedbased on the measured rate. It is also preferable to continue measuringinspiratory flow during and after any drug delivery and to recordinspiratory flow rate and volume before, during and after the release ofdrug. Such reading makes it possible to determine if drug was properlydelivered to the patient.

Each of the parameters discussed above is measured during quantitativespirometry. A patient's individual performance can be compared againsthis personal best data, individual indices can be compared with eachother for an individual patient (e.g. FEV₁ divided by FVC, producing adimensionless index useful in assessing the severity of acute asthmasymptoms), or each of these indices can be compared against an expectedvalue.

Expected values for indices derived from quantitative spirometry arecalculated as a function of the patient's sex, height, weight and age.For instance, standards exist for the calculation of expected indicesand these are frequently reported along with the actual parametersderived for an individual patient during a monitoring event such as aquantitative spirometry test.

General Methodology

The invention comprises aerosolizing a formulation of an insulin analogand inhaling the aerosolized formulation into the lungs. Although theinhalation of insulin which results in the insulin entering thecirculatory system is known correctly dosing the amount of insulindelivered by inhalation has been problematic. The devices, formulationsand methods disclosed herein are useful in solving problems with priormethods. For example, when conventional insulin or human recombinantinsulin is delivered to a patient by inhalation the insulin remains onthe surface of the lung tissue for a considerable period of time, i.e.,does not rapidly enter the circulatory system. The delay between thedelivery of the aerosolized insulin and the eventual entry of thatinsulin into the circulatory system is problematic in that it isdesirable to obtain an immediate effect and thereby quickly lower theblood glucose level. If the blood glucose level is not quickly loweredthe patient may administer additional insulin which in combination withthat already administered will dangerously lower the blood glucoselevel. The present invention endeavors to solve the problem of insulinsequestration in the lung after delivery by inhalation which isaccomplished by the delivery of an insulin analog which rapidlydisassociates into its monomeric form. The preferred insulin analog is amonomeric insulin analog which is formulated in accordance with theformulation described in the 1997 PDR at page 1488 (incorporated hereinby reference). This preferred insulin analog is also referred to hereinas a LysPro insulin analog or simply by the term LysPro which is alsoreferred to herein by the generic name "Humalog." The following providesa description of the conceptual basis of the present invention.

Insulin has been used for over 50 years for the management of diabetesmellitus. Insulin is a naturally occurring hormone which plays aclinical role in glucose metabolism and its absence in patients withType I Diabetes is a fatal illness unless exogenous insulin is used aspart of an insulin replacement therapy program.

Patients have self administered insulin subcutaneously for decades as ameans for managing their diabetes. The total daily dose of insulinrequired by individual patients varies. The availability of portableblood glucose monitors over the last decade has been a significantadvancement in that patients can now measure their own blood glucoselevels in self dose insulin by injection according to their needs. Manythings effect the daily requirement for insulin. These multiple factorsrequire that patients measure blood glucose levels to achieve tightcontrol of their blood glucose.

The Diabetes Control and Complications Clinical Trial (DCCT), amulticenter study designed to evaluate the potential long termbeneficial effects of tight blood glucose control, was recentlycompleted. This study demonstrated that insulin acquiring diabetics whomaintained their serum glucose were then a specific range over time. Hada significantly reduced complication rate including the avoidance of theconsequences of peripheral vascular disease including renal failurechronic diabetic retinopathy and lower extremity problems.

A key element in the attainment of a stable blood glucose level overtime involves the administration of subcutaneously administered insulinprior to meal time.

In this way, blood levels of insulin will appear coincident with theincrease in blood glucose associated with meal digestion. Recombinanthuman insulin, which has been available for over more than 10 years, isavailable in a short acting form (regular insulin) which is appropriatefor self administration by injection prior to meal time. Unfortunately,recombinant human insulin must be dosed by injection approximately onehalf hour prior to meal time in order to insure that a rise in bloodglucose does not occur unopposed by exogenous insulin levels.

The acquirement that recombinant human insulin be injected one half hourprior to meal time is burdensome because it requires that patientsprecisely anticipate the times they will be eating. Eli Lilly hasrecently introduced Humalog (a recombinant human insulin analog), whichis more rapidly absorbed than recombinant human insulin when injectedsubcutaneously. Because it works more quickly than recombinant humaninsulin, Humalog can be given just prior to meal time thereby reducingthe burden on the patient to plan ahead prior to eating.

Recombinant human insulin in aqueous solution is in a hexamericconfiguration. In other words, six molecules of recombinant insulin arenoncovalently associated in a hexameric complex when dissolved in waterin the presence of zinc ions. Studies have demonstrated that hexamericinsulin is not rapidly absorbed from the subcutaneous space. In orderfor recombinant human insulin to be absorbed into circulation, thehexameric form must first associate into dimer and/or a monomeric formsi.e., these forms are required before the material can transit into theblood stream. This requirement for recombinant human insulin todisassociate from hexameric to dimer or mortimeric form prior toabsorption is believed to be responsible for the 30 minutes required fora self administer dose of subcutaneous recombinant human insulin toproduce a measurable therapeutic blood level.

Although Humalog exists in solution as a hexamer, it very rapidlydisassociates into a virtually entirely monomeric form followingsubcutaneous administration. Clinical studies have demonstrated thatHumalog is absorbed quantitatively faster than recombinant human insulinafter subcutaneous administration.

Because insulin must be administered frequently in order to allowpatients to attain a tight degree of control over their serum glucose,the fact that all insulin products currently need to be delivered byinjection is a hindrance to compliance. Results from a DCCT studydemonstrate that insulin should ideally be administered 4-6 times eachday in order for patients to be likely to achieve an adequate level ofblood glucose control to obtain a reduction in complication rateassociated with diabetes. A noninvasive method for the delivery ofinsulin could be beneficial in increasing patient compliance withfrequent self administration of insulin throughout the day.

The noninvasive delivery of proteins and peptides has been an elusivegoal of the drug delivery industry. Because proteins are rapidlydisassociated in the GI tract, oral forms for the delivery of proteinsas tablets or capsules have thus far seen limited success. Inhalationaldrug delivery has been demonstrated to be a viable option for thedelivery of proteins and peptides such as insulin via the lung, see U.S.Pat. No. 5,364,838, issued Nov. 15, 1994.

Recent studies have demonstrated that insulin can be reproduciblyadministered for inhalation to healthy volunteers producing a rapid risein measurable serum glucose level as well as a rapid fall in bloodglucose. U.S. Pat. No. 5,544,646 describes systems for theintrapulmonary delivery of aerosolized aqueous formulations. The systemdescribed allows unit dosed packages of aqueous formulated drug to bedelivered deep into the lung for systemic effect. U.S. Pat. No.5,558,085, Intrapulmonary Delivery of Peptide Drugs illustrates howproteins and peptides can be delivered as fine particle aerosols throughthe lung for systemic effect. U.S. Pat. No. 5,497,763 describes adisposable package for intrapulmonary delivery of aerosolizedformulations allowing sealed packets of preformulated drugs such asinsulin to be inserted by the patient into aerosolization apparatus forproducing fine particle aerosols for deep inhalation.

By quantitatively measuring the inspiratory flow rate and volume duringthe patients inspiratory maneuver while breathing through theaerosolization system, an optimum point for the delivery of a bolus ofaerosolized medication can be determined. U.S. Pat. No. 5,509,404describes intrapulmonary drug delivery within therapeutically relevantinspiratory flow volume values and illustrates how specific inspiratoryflow rate and flow volume criteria can be used to enhance thereproducibility of drugs delivered via the lung for systemic effect.U.S. Pat. No. 5,522,385, Dynamic Particle Size Control for AerosolizedDrug Delivery demonstrates that the parameters of the emitted aerosolcan be varied to optimize the delivery of an inhaled aerosol forsystemic effect.

U.S. patent application Ser. No. 08/754,423, filed Nov. 11, 1996 nowU.S. Pat. No. 5,473,250 issued Apr. 28, 1998 illustrates thatrecombinant human insulin when delivered as an aerosol for deepinhalation into the lung for systemic effect is sequestered in the lungto a significant degree. This U.S. patent application describes howinsulin sequestered within the lung can be made to transit into thesystemic circulation if the patient engages in certain specificinspiratory maneuvers following delivery.

Although the reasons for sequestration of insulin in the lung followingaerosolized delivery are not known, we speculate that, as withsubcutaneous delivery, the disassociation of insulin from hexameric tomonomeric form is an important first step prior to the absorption ofinsulin into the blood stream. A recent controlled experiment conductedby the inventors, quantified the degree to which insulin is sequesteredinto the lung following aerosolized delivery. In this controlledexperiment, the amount of insulin released into the blood streamfollowing aerosol delivery was quantified in cross over fashion with andthen without a forced expiratory maneuver following delivery. This studyillustrated that a significant amount of insulin is consistentlysequestered in the lung following aerosolized delivery.

It is an object of this invention to demonstrate a novel application forHumalog as an insulin analog well suited for pulmonary drug delivery.

It is an object of this invention to demonstrate that Humalog providesunique benefits when delivered via the lung by reducing the degree towhich lung sequestration occurs following aerosolized delivery.

It is an object of this invention to demonstrate that by reducing thesequestration of insulin in the lung following aerosolized delivery bydelivering Humalog in place of recombinant human insulin that Humalogproduces a greater degree of bioavailability as compared to thatobserved after the delivery of a similar quantity of recombinant humaninsulin.

It is an object of this invention to demonstrate that by increasing thebioavailability of the delivered insulin analog Humalog that a morereproducible effect on serum blood glucose can be achieved.

It is another object of this invention to demonstrate that the increasedbioavailability seen after the delivery of Humalog via aerosolizationinto the lung results in a more economical approach to the pulmonarydrug delivery of insulin than offered by the delivery of recombinanthuman insulin to the lung via aerosolization.

Although multiple studies have evaluated the feasibility of the deliveryof recombinant human insulin via the lung as a fine particle aerosol, nostudies have appeared demonstrating that recombinant human insulin issequestered in the lung following aerosolized delivery. Recentlyconducted clinical studies demonstrate that significant sequestration ofrecombinant human insulin is occurring in the lung following aerosoldrug delivery. Although this degree of sequestration can be reversed bycertain specific pulmonary maneuvers as shown in our copendingapplication, now U.S. Pat. No. 5,473,250 issued Apr. 28, 1998 it will bedesirable to substantially reduce or eliminate this sequestrationaltogether.

Because Humalog rapidly disassociates into monomeric insulin, it isuniquely suited for delivery via the lung.

Inhale/Exhale Maneuver

By delivering a monomeric insulin analog the present inventionsubstantially reduces or eliminates the sequestration of drug on thelung. In situations where sequestration still occurs to some extent itis desirable to carry out an inhale/exhale maneuver. This isaccomplished by having the patient inhale maximally and then exhalemaximally, i.e. exhale the forced vital capacity of the lungs. The drugdelivery device of the present invention preferably includes a sensorwhich can be mechanical but preferably electronic. The sensor canmeasure inspiratory flow and volume. Per the present invention thepatient is instructed to inhale maximally from the mouthpiece of thedrug delivery device so that the inhaled airflow can be measured. In asimilar manner the patient is instructed to exhale maximally into themouthpiece so that the rate and volume of the exhale can be measured. Ithas been found by carrying out the inhale-exhale maneuver that the rateat which the insulin deposited on lung tissue enters the circulatorysystem is substantially increased. This is shown dramatically in FIG.15-19. When the amount of insulin entering the circulatory systemincreases the glucose level decreases.

From this point forward it should be noted that for brevity purpose theterm "insulin" is used to cover all forms of insulin and its analogsincluding LysPro insulin. When insulin is delivered by any methodologythe patient must wait until the insulin has its maximum effect beforedelivering more insulin to avoid an insulin overdose. Thus, whendelivering insulin by inhalation the patient must wait until all orsubstantially all of the insulin deposited on lung tissue is absorbedinto the circulatory system before inhaling additional insulin. If thisis not done the patient is dosed with too much insulin such could drivethe blood glucose level down to a dangerously low level. Thus, by usingthe inhale-exhale maneuver of the present invention the patient can moresafely and rapidly obtain the desired effect of the administered insulinon the glucose level.

Although an important aspect of the present invention relates to theinhale-exhale maneuver the invention also includes containers, devicesand methods which provide a non-invasive means of treating diabetesmellitus in a manner which makes it possible to accurately dose theadministration of aerosolized insulin and thereby maintain tight controlover serum glucose levels of a patient suffering from the disease. Thedevice of the invention provides a number of features which make itpossible to achieve the controlled and repeatable dosing procedurerequired for treating diabetes.

Specifically, the device is not directly actuated by the patient in thesense that no button is pushed nor valve released by the patientapplying physical pressure. On the contrary, the device of the inventionprovides that aerosolized insulin formulation is released automaticallyupon receipt of a signal from a microprocessor programmed to send asignal when data is received from a monitoring device such as an airflowrate monitoring device.

A patient using the device withdraws air from a mouthpiece and theinspiratory rate of the patient is measured as is cumulative respiratoryvolume one or more times in a monitoring event which determines apreferred point in an inhalation cycle for the release of a dose ofinsulin. Inspiratory flow is measured and recorded in one or moremonitoring events for a given patient in order to develop an inspiratoryflow profile for the patient. The recorded information is analyzed bythe microprocessor in order to deduce a preferred point within thepatient's respiratory cycle for the release of insulin with thepreferred point being calculated based on the most likely point toresult in a reproducible delivery event. The monitoring devicecontinually sends information to the microprocessor, and when themicroprocessor determines that the optimal point in the respiratorycycle is reached, the microprocessor actuates the opening of the valveallowing release of insulin.

Accordingly, drug is always delivered at a pre-programmed place in therespiratory flow profile of the particular patient which is selectedspecifically to maximize reproducibility of drug delivery and peripheraldispersion of the drug. It is pointed out that the device of the presentinvention can be used to, and actually does, improve the efficiency ofdrug delivery. However, this is not the critical feature. The criticalfeature is the enhanced rate at which insulin is brought into thecirculatory system and the reproducibility of the release of a tightlycontrolled amount of drug at a particular point in the inspiratory cycleso as to assure the delivery of a controlled and repeatable amount ofdrug to the lungs of each individual patient and allow further insulinto be absorbed more quickly if needed.

The combination of automatic control of insulin release, combined withfrequent monitoring events in order to calculate the optimal flow rateand time for the release of insulin, combine to provide a repeatablemeans of delivering insulin to a patient. Because aerosolized insulinformulation is released automatically and not manually, it canpredictably and repeatedly be released in the same amount each time toprovide a preprogrammed measured amount which is desired. Because dosingevents are preferably preceded by monitoring events, the amount ofinsulin released and/or the point in the inspiratory cycle of therelease can be readjusted based on the particular condition of thepatient. For example, if the patient's total volume should change, suchwill be taken into account in the monitoring event by the microprocessorwhich will readjust the amount and/or point of release of the insulin ina manner calculated to provide for the administration of the same amountof insulin to the patient at each dosing event. Because theinhale-exhale maneuver enhances the rate of absorbtion of insulin intothe circulatory system the patient can more quickly control the effectof the insulin on glucose level and determine whether it is necessary toadminister additional insulin.

To obtain controlled repeatable dosing a number of factors arepreferably considered. Specifically, one should adjust:

(1) The amount of insulin delivered after carrying out the inhale-exhalemaneuver of the invention;

(2) the release point within a patient's inspiratory flow rate inside arange of about 0.10 to about 2.0 liters/second preferably about 0.2 toabout 1.8 liters per sec. and more preferably 0.15 to 1.7 liters persec; and within a patient's inspiratory volume of about 0.15 to about2.0 liters preferably 0.15 to 0.8 liters and more preferably 0.15 toabout 0.4 liters;

(3) particle size for systemic delivery in a range of about 0.5 to 6microns and more preferably 0.5 to about 3 microns;

(4) the concentration of the drug in the carrier in the range of fromabout 0.01% to about 12.5%;

(5) the amount of heat added to the air about 20 Joules to about 100Joules and preferably 20 Joules to about 50 Joules per 10 μl offormulation;

(6) the relative volume of air added by patient inhalation per 10 μl offormulation at about 100 ml to 2 l and preferably about 200 ml to 1liter for evaporation and without evaporation 50-750 ml preferably200-400 ml;

(7) the rate of vibration of the porous membrane from 575 to 17,000kilohertz;

(8) pore size to a range of about 0.25 to about 6.0 microns in diameterpreferably 0.5 to 3 microns and more preferably 1-2 microns;

(9) viscosity of the formulation to a range of from about 25% to 1,000%of the viscosity of water;

(10) extrusion pressure in a range of about 50 to 600 psi and preferably100 to 500 psi;

(11) ambient temperature to 15° C. to 30° C. and ambient pressurebetween 1 atmosphere and 75% of 1 atmosphere;

(12) the ratio of liquid carriers to each other to be consistent;

(13) the solubility of drug to carrier to obtain a high concentration ofinsulin in the carrier;

(14) the desiccator to maximize removal of water vapor from air;

(15) the shape of the pore opening to be circular in diameter and aconical in cross-section with the ratio of the diameter of the small tolarge end of the cone being about to 1/2 to 1/20, and the shape of theporous membrane to an elongated oval;

(16) the thickness of the membrane to 5 to 200 microns; preferably 10-50microns;

(17) the membrane to have a convex shape or to be flexible so that itprotrudes outward in a convex shape beyond the flow boundary layer whenformulation is forced through it, and

(18) the firing point to be at substantially the same point at eachrelease for the parameters (1-17), i.e., each release of drug is atsubstantially the same point so as to obtain repeatability of dosing.

There is considerable variability with respect to the amount of insulinwhich is delivered to a patient when the insulin is being administeredby injection.

Patients requiring the administration of injectable insulin usecommercial insulin which is prepared in concentrations of 100 units permilliliter, although higher concentrations up to about 500 units permilliliter can be obtained. It is preferable to use the more highlyconcentrated insulin in connection with the present invention. Ifinsulin containing 500 units of insulin per milliliter is used and apatient is administering 5 units, then the patient will only need toadminister 0.01 milliliters of the concentrated insulin to the lungs ofthe patient to achieve the desired dose.

The symptoms of diabetes can be readily controlled with theadministration of insulin. However, it is extremely difficult, andprobably impossible, to normalize the blood sugar throughout a 24-hourperiod utilizing traditional insulin therapy given as one or twoinjections per day. It is possible to more closely approach normalizedblood sugar levels with the present invention. Improvements are obtainedby smaller, more frequent dosing and by timing dosing relative to meals,exercise and sleep.

The precise amount of insulin administered to a patient variesconsiderably depending upon the degree of the disease and the size ofthe patient. A normal-weight adult may be started on about a 15-20 unitsa day in that the estimated daily insulin production rate innon-diabetic subjects of normal size is approximately 25 units per day.It is preferable to administer approximately the same quantity ofinsulin for several days before changing the dosing regime except withhypoglycemic patients for which the dose should be immediately decreasedunless a clearly evident nonrecurrent cause of hypoglycemia (such as noteating, i.e., missing a typical meal) is present. In general, thechanges should not be more than five to ten units per day. It is typicalto administer about two-thirds of the total insulin daily dosage beforebreakfast and administer the remainder before supper. When the totaldosage reaches 50 or 60 units per day, a plurality of smaller doses areoften required since peak action of insulin appears to be dose related,i.e., a low dose may exhibit maximal activity earlier and disappearsooner than a large dose. All patients are generally instructed toreduce insulin dosage by about 5 to 10 units per day when extra activityis anticipated. In a similar manner, a small amount of extra insulin maybe taken before a meal that contains extra calories or food which is notgenerally eaten by the diabetic patient. The inhalation device of thepresent invention is particularly useful with respect to providing suchsmall amounts of additional insulin.

Several types of insulin formulations are commercially available. Whenlarger doses of insulin must be administered at a single point in time,it may be preferable to administer intermediate or long-acting insulinformulations. Such formulations release some insulin immediately andprovide a more sustained release of the remainder of the insulin overtime. Such formulations are described further below in the "InsulinContaining Formulations" section.

When administering insulin using the inhalation device of the presentinvention, the entire dosing event can involve the administration ofanywhere from one to 25 units, but more preferably involves theadministration of approximately five to ten units. The entire dosingevent may involve several inhalations by the patient with each of theinhalations being provided with multiple bursts of insulin from thedevice. For example, the device can be programmed so as to releaseenough insulin so that approximately one unit of insulin is delivered tothe patient per inhalation or 0.33 units of insulin per burst with threebursts being delivered per inhalation. If ten units are to be delivered,the ten units are delivered by releasing 33 bursts in ten differentinhalations. Such a dosing event should take about 1-2 minutes todeliver 10 units of insulin. Since only small amounts are delivered witheach burst and with each inhalation, even a complete failure to deliverinsulin with a given inhalation or burst is not of great significanceand will not seriously disturb the reproducibility of the dosing event.Further, since relatively small amounts are delivered with eachinhalation and/or burst, the patient can safely administer an additionalunit or two of insulin without fear of overdosing.

There is a differential between the amount of insulin actually releasedfrom the device and the amount of insulin actually delivered to thepatient. The present device is two to ten times more efficient thanconventional inhalation devices (i.e., MDIs or metered dose inhalers)which have an efficiency as low as 10% meaning that as little as 10% ofthe released insulin may actually reach the circulatory system of thepatient. The efficiency of the delivery will vary somewhat from patientto patient and should be taken into account when programming the devicefor the release of insulin.

One of the difficulties with aerosolized delivery of insulin is that thepatient and/or the caregiver cannot determine precisely how much insulinhas entered the circulatory system. Accordingly, if the patient has beendosed with what is believed to be an adequate amount of aerosolizedinsulin and the glucose level remains high one might assume that theaerosolized dose was not properly delivered. For example, the insulinmight have been improperly delivered against the patient's mouthsurfaces or throat where it will not be absorbed into the circulatorysystem. However, it may be that the insulin is properly delivered to thelung (e.g., provided on the outer peripheral areas of the lung) but hasnot yet migrated into the circulatory system. The present inventionprovides a mechanism for more quickly bringing the insulin deposited onlung tissue into the circulatory system. This method involves theinhale-exhale maneuver whereby the patient inhales maximally and thenexhales maximally. The result of carrying out this maneuver isgraphically shown in FIGS. 15-19. Specifically, referring to FIG. 15 theamount of insulin in the blood plasma in terms of microunits permilliliter is plotted over time in minutes. An aerosolized dose ofinsulin is delivered at zero time. At 20 minutes and 40 minutes thepatient is instructed to carry out the inhale-exhale maneuver of theinvention. As can be seen in the graph, just after 20 minutes in timethe plasma level of insulin spikes dramatically. The same result is seenjust after 40 minutes. After both spikes in the insulin level the plasmaglucose level is shown to be reduced.

In FIG. 16 a similar graph is shown where the patient is instructed tocarry out the inhale-exhale maneuver at 20 minutes after the delivery ofinsulin. As shown, shortly after the maneuver is performed the amount ofinsulin found in the plasma spikes dramatically. In FIG. 17 theinhale-exhale maneuver is performed at 40 minutes after delivery. Again,there is shown a dramatic increase in the amount of insulin found in theplasma after the performance of the inhale-exhale maneuver. Similarresults are shown in FIG. 18 at the 40 minute point. FIG. 19 also showsthe delivery of insulin at the zero point in time. In FIG. 19 thepatient carries out the inhale-exhale maneuver at 20 minutes afterdelivery. Shortly after the maneuver is performed the amount of insulinin the plasma dramatically increases. Per FIG. 19 the maneuver is notperformed at the 40 minute interval and, as can be seen, there is noincrease in the amount of insulin found in the plasma. Thus, the FIGS.15-19 clearly demonstrate that the carrying out of the inhale-exhalemaneuver of the invention increases the rate at which insulin is movedfrom the lung tissue into the circulatory system of the patient.

Obese patients are generally somewhat less sensitive to insulin and mustbe provided with higher doses of insulin in order to achieve the sameeffect as normal weight patients. Dosing characteristics based oninsulin sensitivity are known to those skilled in the art and are takeninto consideration with respect to the administration of injectableinsulin. The present invention makes it possible to vary dosing overtime if insulin sensitivity changes and/or if user compliance and/orlung efficiency changes over time.

Based on the above, it will be understood that the dosing or amount ofinsulin actually released from the device can be changed based on themost immediately prior monitoring event wherein the inspiratory flow ofa patient's inhalation is measured. The amount of insulin released canalso be varied based on factors such as timing and timing is, ingeneral, connected to meal times, sleep times and, to a certain extent,exercise times. Although all or any of these events can be used tochange the amount of insulin released from the device and thus theamount of insulin delivered to the patient, ultimately, the amountreleased and delivered to the patient is based on the patient's serumglucose levels. It is important to maintain the serum glucose levels(true) of the patient within acceptable levels (greater than 60 mg/dland less than 125 mg/100 ml and most preferably to maintain those levelsat about 80 mg/100 ml.

Variations in doses are calculated by monitoring serum glucose levels inresponse to known amounts of insulin released from the device. If theresponse in decreasing serum glucose level is higher than with previousreadings, then the dosage is decreased. If the response in decreasingserum glucose level is lower than with previous readings, then thedosing amount is increased. The increases and decreases are gradual andare preferably based on averages (of 10 or more readings of glucoselevels after 10 or more dosing events) and not a single dosing event andmonitoring event with respect to serum glucose levels. The presentinvention can record dosing events and serum glucose levels over time,calculate averages and deduce preferred changes in administration ofinsulin.

As another feature of the invention, the device can be programmed so asto prevent the administration of more than a given amount of insulinwithin a given period of time. For example, if the patient normallyrequires 25 units per day of insulin, the microprocessor of theinhalation device can be programmed to prevent further release of thevalve after 35 units has been administered within a given day. Setting aslightly higher limit would allow for the patient to administeradditional insulin, if needed, due to larger than normal meals and/oraccount for misdelivery of insulin such as due to coughing or sneezingduring an attempted delivery.

The ability to prevent overdosing is a characteristic of the device dueto the ability of the device to monitor the amount of insulin releasedand calculate the approximate amount of insulin delivered to the patientbased on monitoring given events such as airflow rate and serum glucoselevels. The ability of the present device to prevent overdosing is notmerely a monitoring system which prevents further manual actuation of abutton. As indicated above, the device used in connection with thepresent invention is not manually actuated, but is fired in response toan electrical signal received from a microprocessor. Applicant's devicedoes not allow for the release of insulin merely by the manual actuationof a button to fire a burst of insulin into the air.

The microprocessor of applicant's invention can be designed so as toallow for an override feature which would allow for the administrationof additional insulin. The override feature could be actuated in anemergency situation. Alternatively, the override feature could beactuated when the device is electronically connected with a serumglucose level monitoring device which determines that serum glucoselevels increase to dangerously high levels.

The microprocessor of applicant's invention will preferably include atiming device. The timing device can be electrically connected withvisual display signals as well as audio alarm signals. Using the timingdevice, the microprocessor can be programmed so as to allow for a visualor audio signal to be sent when the patient would be normally expectedto administer insulin. In addition to indicating the time ofadministration (preferably by audio signal), the device can indicate theamount of insulin which should be administered by providing a visualdisplay. For example, the audio alarm could sound alerting the patientthat insulin should be administered. At the same time, the visualdisplay could indicate "five units" as the amount of insulin to beadministered. At this point, a monitoring event could take place. Aftercompletion of the monitoring event, administration would proceed and thevisual display would continually indicate the remaining amount ofinsulin which should be administered. After the predetermined dose offive units had been administered, the visual display would indicate thatthe dosing event had ended. If the patient did not complete the dosingevent by administering the stated amount of insulin, the patient wouldbe reminded of such by the initiation of another audio signal, followedby a visual display instructing the patient to continue administration.

Additional information regarding dosing with insulin via injection canbe found within Harrison's--Principles of Internal Medicine (most recentedition) published by McGraw Hill Book Company, New York, incorporatedherein by reference to disclose conventional information regardingdosing insulin via injection.

Drug Delivery with Disposable Container

FIG. 1 is a cross-sectional view of a container 1 of the invention whichis shaped by a collapsible wall 2. The container 1 has an openingcovered by a flexible porous membrane 3 which is covered by a removablelayer 4. The membrane 3 may be rigid and protrude upward in a convexconfiguration away from the formulation 5. When the layer 4 is removedthe wall 2 can be collapsed thereby forcing the insulin formulation 5against the flexible porous membrane 3 which will then protrude outwardin a convex shape.

FIG. 2 is a cross-sectional view of a more preferred embodiment of acontainer 1 of the invention. The container may be in any configurationbut is generally cylindrical and formed out of a single layer ofmaterial which forms the collapsible wall 2. The container 1 includes anopening which leads to an open channel 6 which channel 6 includes anabutment 7 which is broken upon the application of force created byformulation 5 being forced from the container. When the abutment 7 isbroken the formulation 5 flows to an area adjacent to the flexibleporous membrane 3 and is prevented from flowing further in the channel 6by a non-breakable abutment 8.

FIG. 3 is a cross-sectional view of the container 1 of FIG. 2 in use.The wall 2 is being crushed by a mechanical component such as the piston9 shown in FIG. 3. The piston may be driven by a spring, compressed gas,or a motor connected to gears which translate the electric motor'scircle motion to linear motion. The formulation 5 is forced into theopen channel 6 (breaking the abutment 7 shown in FIG. 2) and against andthrough the membrane 3 causing the membrane 3 to protrude outward into aconvex configuration as shown in FIG. 3.

The piston 9 has been forced against the container wall 2 after apatient 10 begins inhalation in the direction of the arrow "I". Thepatient 10 inhales through the mouth from a tubular channel 11. Thevelocity of the air moving through the flow path 29 of the channel 11can be measured across the diameter of the channel to determine a flowprofile 12, i.e., the air flowing through the channel 11 has a highervelocity further away from the inner surface of the channel. The airvelocity right next to the inner surface of the channel 11 (i.e.,infinitely close to the surface) is very slow (i.e., approaches zero). Aflow boundary layer 13 defines a set of points below which (in adirection from the channel center toward the inner surface of thechannel) the flow of air is substantially below the bulk flow rate i.e.,50% or less than the bulk flow rate.

To allow air to flow freely through the channel 11 the upper surface ofthe flexible porous membrane 3 is substantially flush with (i.e., insubstantially the same plane as) the inner surface of the channel 11.Thus, if the membrane 3 remained in place when the formulation 5 movethrough the pores the formulation would be released into the slow movingor substantially "dead air" below the boundary layer 13. However, themembrane 3 protrudes outward through the boundary layer 13 into thefaster moving air. This is desirable in that it aids in avoiding thecoagulation of particles. More specifically, when formulation exits thepores the formulation naturally forms spherical particles. Thoseparticles slow down due to the frictional resistance created by the airthrough which the particles must travel. The particles existing behindthem can face reduced air friction because the preceding particle havemoved the air aside. Thus later released particles catch up with andmerge into the earlier released particles. This can cause a chainreaction resulting in the formation of large particles which can not bereadily inhaled into the lung--e.g., the formation of particles having adiameter of more than about 12.0 microns.

A plan view of a simple embodiment of a drug delivery device 40 of thepresent invention is shown within FIG. 4. The device 40 is loaded andoperates with a plurality of interconnected disposable containers 1which form a package 46. Before describing the details of the individualcomponents of the device 40, a general description of the device and itsoperation is in order.

Conventional metered dose inhalers and nebulizers suffer from a numberof disadvantages. These disadvantages result in the inability to usethese devices to repeatedly deliver the same amount of drug to apatient. The disadvantages are due, in part, to the inability to controlparticle size--especially when the device is used in diverseenvironments with greatly different humidity conditions or whendiffering amounts of drug are delivered into a fixed amount of air orsimilar quantities of drug are delivered into differing amounts of air.By adding sufficient energy to the particles to evaporate any carrierparticle size is reduced to a uniform minimum and any humidityvariations do not affect particle variability. Further the drugdispensing device of the present invention preferably includeselectronic and/or mechanical components which eliminate direct useractuation of drug release. More specifically, the device preferablyincludes a means for measuring inspiratory flow rate and inspiratoryvolume and sending an electrical signal as a result of the simultaneousmeasurement of both (so that drug can be released at the same point eachtime) and also preferably includes a microprocessor which is programmedto receive, process, analyze and store the electrical signal of themeans for measuring flow and upon receipt of signal values withinappropriate limits sending an actuation signal to the mechanical meanswhich causes drug to be extruded from the pores of the porous membrane.

The device 40 shown in FIG. 4 is loaded with a disposable package 46. Touse the device 40 a patient (see FIG. 3) inhales air from the mouthpiece30. The air drawn in through the opening 38 (and optionally thedesiccator 41) flows through the flow path 29 of the channel 11. Thedisposable package 46 is comprised of a plurality of disposablecontainers 1. Each container 1 includes a drug formulation 5 and iscovered by the porous membrane 3. An air-heating mechanism 14 located inthe flow path 29. The air heating mechanism 14 is preferably positionedsuch that all or only a portion of the air flowing through the path 29will pass by the heater, e.g., flow vent flaps can direct any desiredportion of air through the heater 14. The heat is preferably turned onfor 30 sec or less prior to inhalation and turned off after drugdelivery to conserve power.

The device 40 is a hand-held, portable device which is comprised of (a)a device for holding a disposable package with at least one butpreferably a number of drug containers, and (b) a mechanical mechanismfor forcing the contents of a container (on the package) through aporous membrane. The device preferably further includes (c) a heatingmechanism for adding energy to the air flow into which particles arereleased, (d) a monitor, for analyzing the inspiratory flow of apatient, (e) a switch for automatically releasing or firing themechanical means after the inspiratory flow rate and/or volume reaches apredetermined point (f) a means for measuring ambient temperature andhumidity and (g) a source of power e.g., conventional batteries.

The device for holding the disposable package may be nothing more than anarrow opening created between two outwardly extending bars 42 and 82 ormay include additional components such as one or more wheels, sprocketsor rollers notably mounted on the end(s) of such bars. The rollers maybe spring mounted so as to provide constant pressure against thesurface(s) of the package. The device may also include a transportmechanism which may include providing drive power to the roller(s) sothat when they are rotated, they move the package from one container tothe next. The power source 43 driving the roller(s) is programmed viathe microprocessor 26 to rotate the rollers only enough to move thepackage 39 from one container 1 to the next. In order to use the device40, the device 40 must be "loaded," i.e. connected to a package 39 whichincludes drug dosage units having liquid, flowable formulations ofpharmaceutically active insulin therein. The entire device 40 isself-contained, light weight (less than 1 kg preferably less than 0.5 kgloaded) and portable. The power source 43 is preferably in the form ofstandard alkaline batteries. Two 9 volt batteries could supply the heatrequired to heat the air which contacts the particles by about 20° C.for about 100 doses (see FIGS. 5 and 6 re energy required).

The formulation is preferably heated after the formulation has beenforced through the pores of the membrane 3 and aerosolized i.e., energyis preferably added by heating the surrounding air by means of theair-heating mechanism 14 positioned anywhere within the flow path 29.The amount of energy added by the formulation heating mechanism 45 orair-heating mechanism 5 is controlled by the microprocessor 26 based onthe amount of formulation in the container 1 and other factors such asthe concentration of the insulin in the formulation and surroundinghumidity. A hygrometer 50 and thermometer 51 are electrically connectedto the microprocessor 26 allowing the amount of heat to be added to beadjusted based on ambient humidity and temperature.

The carrier may be chosen to provide for greater solubility of insulinin the carrier to obtain a high concentration of insulin and thusrequire less energy to obtain evaporation of the carrier. Dropletshaving a diameter of 6.3 microns can be formed and subjected toevaporation to obtain a particle of one micron in diameter. In therespiratory tract this one micron particle would be expected to grow toa 3 micron particle due to moisture added from the high humidityenvironment of the respiratory tract.

Energy for Evaporation

FIG. 5 is a graph which can be used in calculating the amount of energyneeded to control the size of delivered droplets by controlling theamount of evaporation of carrier from the aerosolized droplets. Thegraph of FIG. 5 contains two types of information, the density ofevaporated water vs. temperature and relative humidity, and the coolingof the air as the water evaporates. The four lines that show a rapidincrease with temperature portray the density of water vapor in air, at25, 50, 75, and 100% relative humidity. The 100% relative humidity curverepresents the maximum number of milligrams of water that can beevaporated per liter of air. The diagonal lines show the temperaturechange of the air as the water droplets evaporate (hereafter called theair mass trajectory curves). As the evaporation proceeds, the densityand temperature will change by moving parallel to these curves. Tocalculate these curves, air density of 1.185 grams/liter, air specificheat of 0.2401 calories/gram, and water latent heat of vaporization of0.583 cal/mg were assumed. These values imply that a liter of air willcool 2 celsius degrees for every milligram of water evaporated, i.e.evaporating 10 micro-liters will cool a liter of air 20 celsius degrees.

FIG. 5 can be used to calculate the amount of preheating needed toevaporate all or substantially all of the carrier in the aerosolizedparticles. As an example, assume the initial ambient conditions are 25°C. and 50% relative humidity. Further, assume that one wants toevaporate 10 μl (10 mgs) of water from an aqueous drug solution.Finally, assume the final relative humidity is 75%. Under theseconditions the aqueous carrier would not evaporate completely. Morespecifically, the final particles would contain approximately equalamounts of drug and water. To calculate the amount of energy to add forthis delivery refer to FIG. 5. Locate the point corresponding to 25° C.and 50% relative humidity. Move up by 10 milligrams, the amount of waterto be evaporated. Now move to the left until the 75% RH curve iscrossed. This occurs at about 29° C. These conditions (75% RH and 29°C.) represent the condition of the air as delivered to the patient.However, still more energy must be added to make up for the cooling ofthe air as the water evaporates. To calculate this amount of heat, moveparallel to the air mass trajectory curves (downward and to the right)until the initial ambient water vapor density is reached, atapproximately 47° C. Thus, sufficient heat to warm the air by 22° C.must be added to achieve near complete evaporation.

FIG. 6 includes similar information with respect to ethanol which can beused in a similar manner. FIG. 5 shows the density of water vapor in airat 25°, 50° and 75° C. and 100% saturation with the air mass trajectoryduring evaporation also shown. The same is shown in FIG. 6 for thedensity of ethanol in air.

The evaporation and growth rates of aqueous droplets is a function oftheir initial diameter, the amount of drug dissolved therein(concentration) and the ambient relative humidity. The determiningfactor is whether the water vapor concentration at the surface of thedroplet is higher or lower than that of the surrounding air. Because therelative humidity at the surface of a particle (i.e. droplet ofaerosolized formulation) is close to 100% for all the low concentrationformulations, a five micron droplet will evaporate to a 1 micron dryparticle in 0% humidity in less than 20 ms. However, if a particle ofdrug 1 micron diameter is inhaled into the lungs (99.5% humidity) it cangrow to about 3 microns in diameter in approximately one second byaccumulating water from the humid lung environment.

Desiccator

The opening 38 may have a desiccator 41 positioned therein whichdesiccator includes a material which removes water vapor from air beingdrawn into the flow path 29. By reducing or more preferably eliminatingwater vapor from the air any water in particles of formulation can bemore efficiently evaporated. Further, the particles delivered to thepatient will have a smaller and more uniform size whether or not energyis added to cause evaporation of water from the particles of theformulation.

The device may include a mouth piece 30 at the end of the flow path 29.The patient inhales from the mouth piece 30 which causes an inspiratoryflow to be measured by flow sensor 31 within the flow path which pathmay be, and preferably is, in a non-linear flow-pressure relationship.This inspiratory flow causes an air flow transducer 37 to generate asignal. This signal is conveyed to a microprocessor which is able toconvert, continuously, the signal from the transducer 37 in theinspiratory flow path 29 to a flow rate in liters per minute. Themicroprocessor 26 can further integrate this continuous air flow ratesignal into a representation of cumulative inspiratory volume. At anappropriate point in the inspiratory cycle, the microprocessor can senda signal to send power from the power source 43 to the air-heatingmechanism 14 which uses information from the hygrometer 50, thermometer51 and particle size and amount of formulation. The microprocessor alsosends a signal to an actuator which causes the mechanical means (e.g.,the piston 24) to force drug from a container of the package into theinspiratory flow path 29 of the device and ultimately into the patient'slungs. After being released, the drug and carrier will pass through aporous membrane 3 to aerosolize the formulation and thereafter enter thelungs of the patient.

When the formulation 5 includes water as all or part of the carrier itis also desirable to include a desiccator 41 within the flow path 29.The desiccator 41 is preferably located at the initial opening 38 butmaybe located elsewhere in the flow path 29 prior to a point in the flowpath when the formulation is fired into the flow path in the form ofaerosolized particles. By drawing air through the desiccator 41 watervapor within the air is removed in part or completely. Therefore, onlydried air is drawn into the remainder of a flow path. Since the air iscompletely dried water carrier within the aerosolized particles willmore readily evaporate. This decreases the energy needs with respect tothe heating devices 14. The desiccator material can be any compoundwhich absorbs water vapor from air. For example, it may be a compoundselected from the group consisting of P₂ O₅, Mg(ClO₄), KOH, H₂ 5O₄,NaOH, CaO, CaCl₂, ZnCl₂, and CaSO₄.

Convex/Flexible Porous Membrane

As shown in FIG. 3 the convex shape that the flexible membrane 3 takeson during use plays an important role. The membrane may be rigid andconvex such as the rigid convex membrane 80 shown in FIG. 8.Alternatively, formulation 5 is forced from the container 1 by forceapplied from a source such as the piston or plate 24 causing theformulation 5 to press against a flexible membrane 3 causing it toconvex outward beyond the plan of the resting surface of the membrane 3and beyond the plan of the inner surface of the channel 11 which isaligned with the surface or membrane 3 when the container 1 is in a drugrelease position. The convex shape of the membrane 3 is shown in FIG. 3.The convex upward distortion of the membrane is important because itpositions the pores of the membrane beyond the boundary layer 13 (shownin FIG. 3) into faster moving air of the channel 29. A number ofcontainers may be connected together to form a package 46 as is shown inFIG. 7. The package 8 is in the form of an elongated tape but can be inany configuration, e.g., circular, square, rectangular, etc.

When pores of the membrane 3 are positioned beyond the boundary layerinto the faster moving air of the channel advantages are obtained.Specifically, the (1) formulation exiting the pores is moved to an airstream where it can be readily carried to the patient and (2) theparticles formed do not exit into slow moving or "dead" air and thus donot rapidly decelerate to a degree such that particles behind them catchup with, collide into and merge with the particle. Particle collisionsare not desirable because they (a) result in particles which are toolarge and cannot be efficiently inhaled into the lung; and (b) result inan aerosol with diverse and unpredictable particle sizes. Either or both(a) and (b) can result in erratic dosing.

The air-heating mechanism 14 heats the surrounding air within the flowpath 29. This causes carrier in the formulation to be evaporated morereadily. If sufficient heat is added the only material reaching thepatient is the substantially dry insulin drug.

The methodology of the present invention could be carried out with adevice that obtains power from a plug-in source. However, the device ispreferably a self-contained, hand-held device which is battery powered.Heating mechanisms of various types can be used. For example, see theheating mechanism in the self-contained, portable sealer for plasticcolostomy bags in French patent 2,673,142 which is incorporated hereinby reference. A portable heater is also taught in European patentapplications 0,430,566 A2 for a "Flavor delivering article" and0,358,002 for "Smoking articles utilizing electric energy," both ofwhich are incorporated herein by reference to disclose and describeheating components powered by batteries.

Supplemental Treatment Methodology

Patients suffering from diabetes mellitus may be treated solely withinsulin as indicated above. However, it is possible to treat suchpatients with a combination of insulin and other drugs such assulfonylureas which act primarily by stimulating release of insulin fromthe beta cells in the pancreas. These drugs have the ability ofincreasing the number of insulin receptors in target tissues and enhanceinsulin-mediated glucose disposal. Some specific sulfonylurea drugswhich can be used in connection with the present invention includeacetohexamide administered in an amount of about 500 to 1,500 mg perday; chlorpropamide, administered in an amount of about 50 to 750 mg perday; tolazamide, administered in an amount of about 0.1 to 1 gram perday; tolbutamide, administered in an amount of about 0.5 to 3 grams perday; glipzide administered in an amount of about 2.5 to 40 mg per dayand glyburide administered in an amount of about 1.25 to 20 mg per day.

In patients who are producing some insulin, the sulfonylurea drugs maybe sufficient to treat the symptoms. Other patients can use acombination of the drugs while administering insulin, while still othersrequire only the administration of insulin. The present invention isbeneficial to each type of patient. Further, the present inventionallows means for eliminating the need for some patients to take insulinby injection. The patients can be provided with oral doses ofsulfonylureas in amounts similar to those indicated above whileadministering small amounts of insulin via the intrapulmonary routeusing the device of the present invention. In accordance with one methodof the invention, the patient is administered a sulfonylurea drug orallyand that treatment is supplemented with insulin administration inrelatively small amounts, e.g., five to ten units per dosing event withtwo to three dosing events per day. Alternatively, the patient isprimarily treated by the administration of insulin via theintrapulmonary route and that treatment is supplemented by the oraladministration of sulfonylureas of the type described above.

Based on the above, it will be understood by those skilled in the artthat a plurality of different treatments and means of administration canbe used to treat a single patient. For example, a patient can besimultaneously treated with insulin by injection, insulin viaintrapulmonary administration in accordance with the present invention,and sulfonylurea drugs, which are orally administered. Benefits can beobtained by the oral administration of sulfonylurea drugs in that theinsulin is naturally released by the patient in a fashion in accordancewith real needs related to serum glucose levels. This natural insulin issupplemented by smaller doses provided by intrapulmonary administrationin accordance with the present invention. Should such prove to beineffective for whatever reason, such as breathing difficulties, suchcould be supplemented by administration via injection.

Drug Delivery Device

The device preferably includes a means for recording a characterizationof the inspiratory flow profile for the patient which is possible byincluding a microprocessor 26 in combination with a read/write memorymeans and a flow measurement transducer. By using such devices, it ispossible to change the firing threshold at any time in response to ananalysis of the patient's inspiratory flow profile, and it is alsopossible to record drug dosing events over time. In a particularlypreferred embodiment the characterization of the inspiratory flow can berecorded onto a recording means on the disposable package.

FIG. 4 shows a cross-sectional plan view of a hand held, self-contained,portable, breath-actuated inhaler device 40 of the present invention.The device 40 is shown with a holder 20 having cylindrical side wallsand a hand grip 21. The holder 20 is "loaded" in that it includes acontainer 1. A plurality of containers 1 (2 or more) are preferablylinked together to form a package 46.

The embodiment shown in FIG. 4 is a simple version of the invention. Thedevice 40 may be manually actuated and loaded. More specifically, thespring 22 may be compressed by the user until it is forced down belowthe actuation mechanism 23. When the user pushes the actuation mechanism23 the spring 22 is released and the mechanical means in the form of aplate 24 is forced upward against a wall 2 of a container 1.Alternatively, a rotating cam (not shown) may be turned by an electricmotor to crush the container 1 and force the contents 5 out via amembrane 3. The amount of force applied (and rate of force applied byadjusting the length of piston stroke) can be adjusted to expel all ofthe contents or, in certain situations, only a portion of the contentse.g., 25%. When the container 1 is compressed its contents are forcedout through the membrane 3 and aerosolized and the container andmembrane are discarded-not reused. Two additional containers 1 shown tothe left are unused. The device of FIG. 4 would not require the use oflow boiling point propellants such as low boiling point fluorocarbons.Numerous additional features and advantages of the present invention canbe obtained by utilizing the monitoring and electronic componentsdescribed below.

It is important to note that a variety of devices can be used in orderto carry out the methodology of the present invention. However, thedevice must be capable of aerosolizing a drug formulation in a containerand preferably does such by forcing formulation through a porousmembrane with the release point based on pre-programmed criteria whichmay be mechanically set or electronically set via criteria readable bythe microprocessor 26. The details of the microprocessor 26 and thedetails of other drug delivery devices which include a microprocessorand pressure transducer of the type used in connection with the presentinvention are described and disclosed within U.S. Pat. No. 5,404,871,issued Apr. 11, 1995, entitled "Delivery of Aerosol Medications forInspiration" which patent is incorporated in its entirety herein byreference, and it is specifically incorporated in order to describe anddisclose the microprocessor and program technology used therewith. Thepre-programmed information is contained within a nonvolatile memorywhich can be modified via an external device. In another embodiment,this pre-programmed information is contained within a "read only" memorywhich can be unplugged from the device and replaced with another memoryunit containing different programming information. In yet anotherembodiment, microprocessor 26, containing read only memory which in turncontains the pre-programmed information, is plugged into the device. Foreach of these three embodiments, changing the programming of the memorydevice readable by microprocessor 26 will radically change the behaviorof the device by causing microprocessor 26 to be programmed in adifferent manner. This is done to accommodate different drugs fordifferent types of treatment.

Microprocessor 26 sends signals via electrical connection 27 toelectrical actuation device 28 which actuates the means 23 which firesthe mechanical plate 24 forcing drug formulation in a container 1 to beaerosolized so that an amount of aerosolized drug is delivered into theinspiratory flow path 29 when the flexible membrane 3 protrudes outwardthrough the flow boundary layer. A signal is also sent to the heater 14to add heat energy to the air in the flow path 29. The device 28 can bea solenoid, motor, or any device for converting electrical to mechanicalenergy. Further, microprocessor 26 keeps a record of all drug dosingtimes and amounts using a read/write non-volatile memory which is inturn readable by an external device. Alternatively, the device recordsthe information onto an electronic or magnetic strip on the package 1.The recorded information can be read later by the care-giver todetermine the effectiveness of the treatment. In order to allow for easeof use, it is possible to surround the inspiratory flow path 29 with amouth piece 30.

The electrical actuation means 28 is in electrical connection with theflow sensor 31 which is capable of measuring a flow rate of about 0 toabout 800 liters per minute. It should be noted that inhalation flowrates are less than exhalation rates, e.g. max for inhalation 200 lpmand 800 lpm for exhalation. A variety of different types of flow sensorsmay be used as per U.S. Pat. No. 5,394,866, issued Mar. 7, 1995, U.S.Pat. No. 5,404,871, issued Apr. 11, 1995 and U.S. Pat. No. 5,450,336,issued Sep. 12, 1995, which are incorporated herein by reference. Theflow sensor 31 includes screens 32, 33 and 34 which are positionedapproximately 1/4" apart from each other but may be comprised of asingle screen or include a non-linear flow path. It is preferable toinclude the desiccator 41 at a point prior to the screens 32, 33 and 34in the flow path so that the elimination of water vapor is considered inany measurement.

As shown in FIG. 4 the flow sensor 31 is made up of a number ofcomponents including the transducer 37 and the individual screens 32, 33and 34. Information from sensor 31 is conveyed via the connecting line39 to the microprocessor 26. In order to carry out the inhale-exhalemaneuver of the invention it is preferable to use the sensor 31 inconnection with the microprocessor 26 which can signal the patient thata maximal inhale maneuver and a maximal exhale maneuver has beencorrectly accomplished. The signal can be an audio signal, visualsignal, or both. For example, the device can issue a sound when thedevice has sensed that a maximal inhale maneuver has been accomplishedor flash a green light. If the inhale maneuver was not sensed to be amaximal maneuver the sound will not actuate and the light will not go onor will be a red light. The same is true with respect to the exhalemaneuver. The device can be individually set for each patient in thateach patient will have a different lung volume and rate at which thatlung volume can be inhaled and exhaled. Preferably, the device isindividually set by the caregiver. However, devices may be preset forindividuals which are judged to have lung volumes of particular sizese.g., 3 liters, 4 liters, 5 liters, 6 liters in total lung volume. Thedevice can be used to (1) coach a patient to correctly perform theinhale-exhale manuever, (2) deliver drug or (3) both (1) and (2).

Tubes 35 and 36 open to the area between the screens 32, 33 and 34 withthe tubes 35 and 36 being connected to a conventional differentialpressure transducer 37. Another transducer designed to measure outflowthrough the opening 38 is also preferably included or the flow sensor 31is designed so that the same components can measure inflow and outflow.When the user draws air through inspiratory flow path 29, air is passedthrough the screens 32, 33 and 34 and the air flow can be measured bythe differential air pressure transducer 37. Alternatively, other meansto measure pressure differential related to air flow, such as aconventional measuring device in the air way, may be used. The flowsensor 31 is in connection with the electrical actuation means 28 (viathe connector 39 to the processor 26), and when a threshold value of airflow is reached (as determined by the processor 26), the electricalactuation means 28 fires the release of a mechanical means 23 releasingthe plate 24 which forces the release of formulation from a container 1so that a controlled amount of insulin is delivered to the patient. Themicroprocessor 26 is optionally connected to an optionally presentvibrating device 45 which may be activated.

Vibration Device

The vibration device 45 creates ultrasonic vibrations which arepreferably at right angles to the plane of the membrane 3. The device 45may be in the form of a piezoelectric ceramic crystal or other suitablevibration mechanism. A vibrating device 45 in the form of apiezoelectric crystal may be connected to the porous membrane by meansof an attenuator horn or acoustic conduction mechanism, which whencorrectly matched with the piezoelectric crystal frequency, efficientlytransmits ultrasonic oscillations of the piezoelectric crystal to theresonance cavity and the porous polycarbonate membrane and if sizedcorrectly permits the ultrasonic energy to be focused in a polycarbonatemembrane 3 allowing for maximum use of the energy towards aerosolizingthe liquid formulation 5. The size and shape of the attenuator horn isnot of particular importance. It is preferred to maintain a relativelysmall size in that the device is hand held. The components are chosenbased on the particular material used as the porous material, theparticular formulation used and with consideration of the velocity ofultrasonic waves through the membrane to achieve a harmonic relationshipat the frequency being used.

A high frequency signal generator drives the piezoelectric crystal. Thisgenerator is capable of producing a signal having a frequency of fromabout 575 kilohertz (Khz) to about 32,000 kilohertz, preferably 1,000 to17,000 kilohertz, more preferably 2,000 to 4,000 kilohertz. The poweroutput required depends upon the amount of liquid being nebulized perunit of time and the area and porosity of the membrane (generallycomprised of a polymeric plastic-like material) used for producing thedrug dosage unit and/or the efficiency of the connection.

Vibration is applied while the formulation 5 is being forced from thepores of the polycarbonate membrane 3. The formulation can beaerosolized with only vibration i.e., without applying pressure.Alternatively, when vibration is applied in certain conditions thepressure required for forcing the liquid out can be varied depending onthe liquid, the size of the pores and the shape of the pores but isgenerally in the range of about 50 to 600 psi, preferably 100 to 500 psiand may be achieved by using a piston, roller, bellows, a blast offorced compressed gas, or other suitable device. The vibration frequencyused and the pressure applied can be varied depending on the viscosityof the liquid being forced out and the diameter and length of theopenings or pores.

It is desirable to force formulation through the porous membrane with arelatively low pressure e.g., pressure less than 500 psi in that lowerpressure reduces the chance of breaking the membrane during the releaseof formulation and makes it possible to make a thinner membrane. Thethinner membranes make it easier to make small holes in that the holesor pores of the membrane are created using a focussed LASER. It ispossible to reduce the pressure further by making the holes conical incross-section. A LASER with a conical focus is used to burn holesthrough the membrane. The larger diameter of the conical shape ispositioned next to the formulation and the smaller diameter opening isthe opening through which the formulation ultimately flows. The ratio ofthe smaller opening to the diameter of the larger opening is in therange of about 1:2 to about 1:20 i.e., the larger opening is between 2and 20 times the diameter of the smaller opening. By creating conicalopenings wherein the smaller end of the cone has a diameter of less than6 microns it is possible to produce particles which have a diameter ofless than 12 microns and it is also possible to force the formulationthrough the pores using a pressure of less than 500 psi. The small endof the conical opening preferably has a diameter of less than 3 micronsfor systemic delivery and less than 5 microns for pulmonary delivery andthe pressure used for forcing formulation through the pores ispreferable less than 350 psi.

When small aerosolized particles are forced into the air, the particlesencounter substantial frictional resistance. This may cause particles toslow down more quickly than desired and may result in particlescolliding into each other and combining, which is undesirable withrespect to maintaining the preferred particle size distribution withinthe aerosol. In order to aid in avoiding the particle collision problem,it is possible to include a means by which air flow and the flexiblemembrane 3 prevent collisions. Specifically, the patient inhales therebycreating an air flow toward the patient over the protruding membrane 3.The air flow carries the formed particles along and aids in preventingtheir collision with each other. The shape of the container opening, theshape of the membrane covering that opening, as well as the positioningand angling of the flow of air through the channel 11 relative to thedirection of formulation exiting the pores of the membrane 3 can bedesigned to aid in preventing particle collision. It is desirable toshape the opening and matching membrane so as to minimize the distancebetween any edge of the opening and the center of the opening.Accordingly, it is not desirable to form a circular opening which wouldmaximize the distance between the outer edges of the circle and thecenter of the circle, whereas it is desirable to form an elongatednarrow rectangular opening covered by a rigid membrane 80 as shown inFIG. 8. Using such a configuration makes it possible to better utilizethe air flow relative to all of the particles of formulation beingforced form the pores of the membrane 3. When a circular opening isused, particles which are towards the center of the circle may not becarried along by the air being drawn over the membrane 3 and willcollide with each other. The elongated rectangle could be formed in acircle, thereby providing an annular opening and air could be forcedoutward from the outer and inner edges of the circle formed. Furtherdetails regarding such are described in U.S. patent application Ser. No.08/247,012, filed May 20, 1994 (now U.S. Pat. No. 5,544,646 issued Aug.13, 1996 which is incorporated herein by reference to disclose anddescribe such.

Operation of the Device 40

The device of FIG. 4 shows all of the components present within thesingle, hand-held, portable breath actuated device, e.g. themicroprocessor 26 and flow sensor 31 used to provide the electronicbreath actuated release of drug. The device of FIG. 4 includes a holdingmeans and mechanical means and preferably operates electronically, i.e.the actuation means is preferably not directly released by the user. Thepatient inhales through inspiratory flow path 29 which can form a mouthpiece 30. Air enters the device via the opening 38. The inhaling iscarried out in order to obtain a metering event using the differentialpressure transducer 37. Further, when the inspiratory flow meets athreshold of a pre-programmed criteria, the microprocessor 26 sends asignal to an actuator release electrical mechanism 28 which actuates themechanical means 23, thereby releasing a spring 22 and plate 24 orequivalent thereof, forcing aerosolized formulation into the channel 11,and out of the membrane 3 into the flow path 29 where the airsurrounding the particles is optionally heated by the air heater 14.Further details regarding microprocessors 26 of FIG. 4 are describedwithin U.S. Pat. No. 5,394,866, issued Mar. 7, 1995, entitled "AnAutomatic Aerosol Medication Delivery System and Methods", which isincorporated herein by reference in its entirety and specificallyincorporated in order to describe and disclose flow measurements, themicroprocessor and program technology used therewith.

Microprocessor 26 of FIG. 4 includes an external non-volatile read/writememory subsystem, peripheral devices to support this memory system,reset circuit, a clock oscillator, a data acquisition subsystem and avisual annunciator subsystem. The discrete components are conventionalparts which have input and output pins configured in a conventionalmanner with the connections being made in accordance with instructionsprovided by the device manufacturers. The microprocessor used inconnection with the device of the invention is designed and programmedspecifically so as to provide controlled and repeatable amounts ofinsulin to a patient upon actuation. The microprocessor must havesufficient capacity to make calculations in real time. Adjustments canbe made in the program so that when the patient's inspiratory flowprofile is changed such is taken into consideration. This can be done byallowing the patient to inhale through the device as a test (monitoringevent) in order to measure air flow with preferred drug delivery pointsdetermined based on the results of several inhalations by eachparticular patient. This process can be readily repeated when theinspiratory flow profile is changed for whatever reason. When thepatient's lung function has decreased the program will automaticallyback down in terms of the threshold levels required for release of drug.This "back down" function insures drug delivery to a patient in need butwith impaired lung function. Determination of optimal drug deliverypoints in the inspiratory flow can be done at each dosing event, daily,weekly, or with the replacement of a new cellular array in the device.

The microprocessor 26 of the present invention, along with itsassociated peripheral devices, can be programmed so as to preventtriggering the actuation mechanism 28 more than a given number of timeswithin a given period of time. This feature makes it possible to preventoverdosing the patient. The overdose prevention feature can beparticularly designed with each individual patient in mind or designedwith particular groups of patients in mind. For example, themicroprocessor can be programmed so as to prevent the release of morethan approximately 30 units of insulin per day when the patient isnormally dosed with approximately 25 units of insulin drug per day. Thedevice can be designed to switch off this lock-out function so thatinsulin can be delivered in an emergency situation.

The device can be used as a sensor alone. More specifically, the insulincan be inhaled from a separate device such as from a dry powder inhaler.Thereafter, the sensor portion of the device is made use of in order toperform the inhale-exhale maneuver of the invention. The inhale-exhalemaneuver of the invention can be performed a plurality of times atdifferent timed intervals after the delivery of aerosolized insulin. Theinhale-exhale manuever can be carried out at anytime after delivery asneeded by the patient to reduce glucose levels. In one embodiment theinhale-exhale maneuver is performed at 20 minutes and again at 40minutes after aerosolized delivery of insulin. However, the maneuver canbe performed at 1 minute intervals, 5 minute intervals, 10 minuteintervals, 20 minute intervals, or 30 minute intervals after delivery ofan aerosolized dose of insulin.

The microprocessor 26 of the invention can be connected to externaldevices permitting external information to be transferred into themicroprocessor of the invention and stored within the non-volatileread/write memory available to the microprocessor. The microprocessor ofthe invention can then change its drug delivery behavior based on thisinformation transferred from external devices. All of the features ofthe invention may be provided in a portable, programmable,battery-powered, hand-held device for patient use which has a size whichcompares favorably with existing metered dose inhaler devices.

The microprocessor 26 of the present invention is programmed so as toallow for monitoring and recording data from the inspiratory flowmonitor without delivering drug. This is done in order to characterizethe patient's inspiratory flow profile in a given number of monitoringevents, which monitoring events preferably occur prior to dosing events.After carrying out a monitoring event, the preferred point within theinspiratory cycle for drug delivery can be calculated. This calculatedpoint is a function of measured inspiratory flow rate as well ascalculated cumulative inspiratory flow volume. This information isstored and used to allow activation of the electronic actuation meanswhen the inhalation cycle is repeated during the dosing event.

Treatment Via Insulin Analogs

The methodologies of the present invention can be carried out using anytype of insulin, although they are preferably carried out usingrecombinantly produced human insulin. Insulin extracted from animalsources such as bovine or porcine sources can be used. More recently,insulin analogs have been developed. More specifically, novel peptideshave been developed wherein the amino acid sequence of the peptides issubstantially the same as the amino acid sequence of naturally occurringhuman insulin but for small changes substituting one amino acid foranother. These small changes can have important physiological effectswith respect to the treatment of diabetes.

Other general types of insulin analogs are presently used. One type ofnew analog is sold by Lilly under the name insulin lispro and thisanalog is absorbed faster after subcutaneous injection. Another type ofinsulin analog is referred to as superactive insulin. In general,superactive insulin has increased activity over natural human insulin.Accordingly, such insulin can be administered in substantially smalleramounts while obtaining substantially the same effect with respect toreducing serum glucose levels. Another general type of analog isreferred to as hepatospecific insulin. Hepatospecific insulin analogsare more active in the liver than in adipose tissue and offer severaladvantages over currently available insulin therapy. Hepatospecificanalogs provide preferential hepatic uptake during peripheralsubcutaneous administration, thereby mimicking, more closely, themetabolic balance between the liver and the peripheral tissues.Obtaining the correct metabolic balance is an important part of propertreatment of diabetics and administration via the intrapulmonary routeshould provide advantages over intermuscular injection with respect toobtaining such a balance. It may be desirable to include mixtures ofconventional insulin with insulin lispro or with insulin which ishepatospecific and/or with superactive insulin analogs. Hepatospecificanalogs are disclosed and described within published PCT applicationWO90/12814, published Nov. 1, 1990, which application is incorporatedherein by reference for its disclosure of such hepatospecific insulinanalogs and in order to disclose other information cited within theother publications referred to within WO90/12814.

U.S. patent application Ser. No. 074,558 discloses a superactive humaninsulin analog, 10-Aspartic Acid-B! human insulin, which has increasedactivity over natural human insulin. Specifically, 10-Aspartic Acid-B!human insulin was determined to be 4 to 5 times more potent than naturalinsulins. U.S. patent application Ser. No. 273,957 and InternationalApplication Serial No. PCT/US88/02289 disclose other superactive insulinanalogs, des-pentapeptide (B26-B30)- Asp^(B10), Tyr^(B25)-α-carboxamide! human insulin, (B26-B30)- Glu^(B10), Tyr^(B25)-α-carboxamide! human insulin, and further insulin analogs of theformula des (B26-B30)- X^(B10), Tyr^(B25) -α-carboxamide! human insulin,in which X is a residue substituted at position 10 of the B chain. Theseinsulin analogs have potencies anywhere from 11 to 20 times that ofnatural human insulin. All of the above-described insulin analogsinvolve amino acid substitutions along the A or B chains of naturalhuman insulin, which increase the potency of the compound or changeother properties of the compound.

Other than Lyspro the insulin analogs are not presently used for thetreatment of patients on a commercial scale. However, insulin lispro andother insulin analogs being developed could be used with the presentinvention in that the present invention can be used to provide variabledosing in response to currently measured serum glucose levels. Further,since many insulin analogs are more potent than conventional insulin,their delivery via the intrapulmonary route is particularly convenient.

Method of Administration

The method and device of the invention provides a number of featureswhich make it possible to achieve the controlled and repeatable dosingprocedure required for the treating of diabetes (which is lifethreatening) with insulin. First, the membrane is permanently convex oris flexible and protrudes into fast moving air aiding the elimination ofparticle collisions. Second, the invention makes it possible toeliminate any carrier from the aerosolized particles solution de eitherinsulin solution droplets or substantial dry insulin particles to apatient which particles can be manufactured to have a uniform size. Bydelivering particles of uniform size repeatability of dosing is enhancedregardless of the surrounding environment, e.g. different humidityconditions. Third, the device makes it possible to administer drug atthe same point with respect to inspiratory flow rate and inspiratoryvolume at each drug delivery point thereby improving repeatability ofdosing.

The method of the invention involves the release of a liquid, flowableinsulin formulation from individual disposable containers which may beinterconnected in a package. This is desirable in that the liquid,flowable drug is packaged under a sterile environment and therefore doesnot require and preferably does not include additional materials such asantifungal, bacteriostatics, and preservatives which would normally berequired in a liquid formulation if the formulation was to be opened,exposed to air, closed and later used again. A new container andmembrane are used for each release of drug. Thus, the membrane andcontainer are disposable thereby preventing clogging of pores whichtakes place with reuse. The invention does not require the use of lowboiling point propellants such as low boiling point fluorocarbons. Theuse of such low boiling point propellants in conventional metered doseinhaler devices is desirable because such propellants eliminate the needfor preservatives, antifungal and bacteriostatic compounds. However,there are potential environmental risks to using low boiling pointfluorocarbons. Accordingly, the present invention provides potentialenvironmental benefits and would be particularly useful if governmentregulations prevented further use of devices which dispensed low boilingpoint fluorocarbons.

In addition to environmental advantages, the present invention offersadvantages due to the relatively slow speed at which the aerosoldispersion is delivered to the patient. A conventional metered doseinhaler device discharges the aerosol outward at a relatively high rateof speed which causes a large amount of the aerosol particles to makecontact with the inside of the patient's mouth and the back of thepatient's throat. This decreases the amount of drug actuallyadministered to the patient's lungs as compared with the present system,wherein the aerosol is delivered at a relatively slow rate of speed andcan be inhaled slowly by the patient.

The method preferably uses a drug delivery device which is not directlyactuated by the patient in the sense that no button is pushed nor valvereleased by the patient applying physical pressure. On the contrary, thedevice of the invention provides that the actuation mechanism whichcauses drug to be forced from a container is fired automatically uponreceipt of a signal from a microprocessor programmed to send a signalbased upon data received from a monitoring device such as an airflowrate monitoring device. A patient using the device withdraws air from amouthpiece and the inspiratory rate, and calculated inspiratory volumeof the patient is measured simultaneously one or more times in amonitoring event which determines an optimal point in an inhalationcycle for the release of a dose of any desired drug. Inspiratory flow ispreferably measured and recorded in one or more monitoring events for agiven patient in order to develop an inspiratory flow profile for thepatient. Recorded information is preferably analyzed by themicroprocessor in order to deduce a preferred point within the patient'sinspiratory cycle for the release of drug with the preferred point beingcalculated based on the most likely point to result in a reproducibledelivery event.

A flow rate monitoring device continually sends information to themicroprocessor, and when the microprocessor determines that the optimalpoint in the respiratory cycle is reached, the microprocessor actuates acomponent which fires a mechanical means (and activates the vibrationdevice) which causes drug to be forced out of the container andaerosolized. Accordingly, drug is repeatedly delivered at apre-programmed place in the inspiratory flow profile of the particularpatient which is selected specifically to maximize reproducibility ofdrug delivery and peripheral deposition of the drug. It is pointed outthat the device of the present invention can be used to, and actuallydoes, improve the efficiency of drug delivery. However, this is not themost important feature. A more important feature is the reproducibilityof the release of a tightly controlled amount of drug (with a narrowrange of particle size) repeatedly at the same particular point in therespiratory cycle so as to assure the delivery of a controlled andrepeatable amount of drug to the lungs of each individual patient, i.e.intrapulmonary drug delivery with tightly controlled dosing.

The heating component(s) and/or the desiccator to remove water vaporsaid in providing repeatability in dosing in that the particles reachingthe patient will have the same size regardless of the surroundinghumidity. By keeping the particle size the same at each dosing event theparticles deposit at the same general area of the lung at each event.These features improve repeatability along with automatic control of thedrug release mechanism, combined with frequent monitoring events inorder to calculate the optimal flow rate and time for the release ofdrug. Further, the particles will have uniform size in that all carrieris removed regardless of the humidity of the surrounding environment.Because the drug release mechanism is fired automatically and notmanually, it can be predictably and repeatedly fired at that same pointin the inspiratory cycle. Because dosing events are preferably precededby monitoring events, the point in the inspiratory cycle of the releasecan be readjusted based on the particular condition of the patient. Forexample, patients suffering from asthma have a certain degree ofpulmonary insufficiency which may well change with the administration ofdrug. These changes will be taken into account in the monitoring eventby the microprocessor which will readjust the point of release of thedrug in a manner calculated to provide for the administration of anamount of insulin to the patient presently needed by the patient at eachdosing event.

When administering drug using the inhalation device of the presentinvention, the entire dosing event can involve the administration ofanywhere from 10 μl to 10 ml of drug formulation, but more preferablyinvolves the administration of approximately 50 μl to 1,000 μl of drugformulation. Very small amounts of drug (e.g., nanogram amounts) may bedissolved or dispersed within a pharmaceutically acceptable, liquid,excipient material to provide a liquid, flowable formulation which canbe readily aerosolized. The container will include the formulationhaving insulin therein in an amount of about 0.5 unit to 5 units, morepreferably about 1 unit. The large variation in the amounts which mightbe delivered are due to different delivery efficiencies for differentdevices, formulations and different patients needs.

The entire dosing event may involve several inhalations by the patientwith each of the inhalations being provided with drug from the device.For example, the device can be programmed so as to release the contentsof a single container or to move from one container to the next on apackage of interconnected containers. Delivering smaller amounts fromseveral containers can have advantages. Since only small amounts aredelivered from each container and with each inhalation, even a completefailure to deliver drug with a given inhalation is not of greatsignificance and will not seriously disturb the reproducibility of thedosing event. Further, since relatively small amounts are delivered witheach inhalation, the patient can safely administer a few additionalunits of insulin without fear of overdosing.

In addition to drug potency and delivery efficiency, drug sensitivitymust be taken into consideration. The present invention makes itpossible to vary dosing over time if sensitivity changes and/or if usercompliance and/or lung efficiency changes over time.

Based on the above, it will be understood that the dosing or amount ofinsulin actually released from the device can be changed based on themost immediately prior monitoring event wherein the inspiratory flow ofa patient's inhalation is measured.

One of the important features and advantages of the present invention isthat the microprocessor can be programmed to take a number of differentcriteria into consideration with respect to dosing times. For example,the microprocessor can be programmed so as to include a minimum timeinterval between doses i.e. after a given delivery another dose cannotbe delivered until a given period of time has passed. Secondly, thetiming of the device can be programmed so that it is not possible toexceed the administration of a set maximum amount of drug within a giventime. For example, the device could be programmed to prevent dispersingmore than ten units of insulin within one hour for a patient with lowinsulin requirements, or more for a patient requiring a large dose ofinsulin. More importantly, the device can be programmed to take bothcriteria into consideration. Thus, the device can be programmed toinclude a minimum time interval between doses and a maximum amount ofdrug to be released within a given time period. For example, themicroprocessor could be programmed to allow the release of a maximum often units of insulin during an hour which could only be released inamounts of one unit with each release being separated by a minimum offive minutes.

The dosing program can be designed with some flexibility. For example,if the patient normally requires 25 units per day of insulin, themicroprocessor can be programmed to provide a warning after 25 unitshave been administered within a given day and to continue the warningthereafter to alert the user of possible overdoses. By providing awarning and not a lock-out, the device allows for the patient toadminister additional insulin, if needed, due to a decreased lungfunction, a different diet, and/or account for misdelivery of insulinsuch as due to coughing or sneezing during an attempted delivery.

The ability to prevent overdosing is a characteristic of the device dueto the ability of the device to monitor the amount of insulin releasedand calculate the approximate amount of insulin delivered to the patientbased on monitoring a variety of lung function parameters. The abilityof the present device to prevent overdosing is not merely a monitoringsystem which prevents further manual actuation of a button. As indicatedabove, the device used in connection with the present invention is notmanually actuated, but is fired in response to an electrical signalreceived from a microprocessor (which received data from a monitoringdevice such as a device which monitors inspiratory flow) and allows theactuation of the device upon achieving an optimal point in a inspiratorycycle. When using the present invention, each actuation of the devicewill administer drug to the patient in that the device is fired inresponse to patient inhalation. More specifically, the preferredembodiment of the device does not allow for the release of insulinmerely by the manual actuation of a button to fire a burst of insulininto the air or a container.

A variety of different embodiments of the dispersion device of theinvention are contemplated. In accordance with one embodiment it isnecessary to carry out manual cocking of the device. This means thatenergy is stored such as by retracting a spring so that, for example, apiston can be positioned below the drug containing container. In asimilar manner a piston connected to a spring can be withdrawn so thatwhen it is released it will force air through the air dispersion vents.Automatic cocking of forced storing systems for both the drugformulation and the air flow may be separate or in one unit. Further,one may be manual whereas the other may be done automatically. Inaccordance with one embodiment the device is cocked manually but firedautomatically and electronically based on monitoring the patientsinspiratory flow. The formulation may be physically moved through theporous membrane in a variety of different ways. Formulation may beforced through the membrane by a piston or, without applying force tothe formulation, the membrane being vibrated at frequencies sufficientto create an aerosol. A combination of forced extrusion and vibrationcould be used.

The microprocessor 26 of the present invention preferably includes atiming device. The timing device can be electrically connected withvisual display signals as well as audio alarm signals. Although insulinis generally administered as needed the timing device and microprocessorcan be programmed so as to allow for a visual or audio signal to be sentto the patient at times when the patient would be normally expected toadminister insulin. In addition to indicating the time of administration(preferably by audio signal), the device can indicate the amount ofinsulin which should be administered by providing a visual display. Forexample, the audio alarm could sound alerting the patient that insulinshould be administered. At the same time, the visual display couldindicate "one dosage unit" as the amount of drug (number of containers)to be administered. At this point, a monitoring event could take place.After completion of the monitoring event, administration would proceedand the visual display would continually indicate the remaining amountof insulin which should be administered. After the predetermined dose(indicated number of containers) had been administered, the visualdisplay would indicate that the dosing event had ended. If the patientdid not complete the dosing event by administering the stated amount ofdrug, the patient would be reminded of such by the initiation of anotheraudio signal, followed by a visual display instructing the patient tocontinue administration.

Additional information regarding dosing insulin can be found withinHarrison's--Principles of Internal Medicine (most recent edition) andthe Drug Evaluation Manual, 1993 (AMA-Division of Drugs and Toxicology),both of which are published by McGraw Hill Book Company, New York,incorporated herein by reference to disclose conventional informationregarding dosing of insulin.

Repeatable Dosing

The device 40 schematically shown within FIG. 4 can be specificallyoperated as follows. A container 1 is loaded into the device 6. Thedevice is then armed meaning that the piston such as the spring-loadedpiston 24 is cocked (i.e., the spring is compressed to a ready position.(The container 1 can be squeezed by a cam rotated by an electric motor).If applicable another piston (not shown) used to compress the liquidformulation in a dual container system is cocked. Further, a container 1of the package is moved into position and any cover is stripped off ofthe porous membrane 3. Thereafter, the patient withdraws air from themouthpiece 30 and the patient's inhalation profile is developed usingthe microprocessor 26. After the inhalation profile is determined, themicroprocessor calculates a point within the inhalation profile at whichthe drug should be released in order to maximize repeatability of thedosing, e.g. by plotting a curve of breath velocity versus time anddetermining the point on the curve most likely to provide repeatabilityof dosing. However, in order to carry out methodology in accordance withthe present invention it is not necessary to plot any curve of breathvelocity versus time. The device can be set so that the dose will berepeatedly released at approximately the same point with respect toinspiratory flow rate and inspiratory volume. If the device repeatedlyfires at the same inspiratory flow rate and inspiratory volume each timethe patient will receive substantially the same dose to the lung. Bothcriteria must be measured and used for firing to obtain repeatability.

The microprocessor of the present invention can be programmed to releasedrug based on all or any of the following parameters.

(1) Delivery should be at an inspiratory flow rate inside a range ofabout 0.10 to about 2.0 liters per second (efficiency can be obtained bydelivering at a flow rate in a range of 0.2 to about 1.8 liters persecond and more preferably 0.15 to 1.7 liters per second). Repeatabilityof the delivery is obtained by releasing at substantially the sameinspiratory flow rate at each drug release.

(2) Delivery should be at a point within a patient's inspiratory volumeof about 0.05 to about 2.0 liters (further efficiency of delivery can beobtained by delivering within a range of 0.15 to 0.8 liters and morepreferably 0.15 to about 0.4 liters). Repeatability of delivery isobtained by delivering at the same inspiratory volume at each release ofdrug.

(3) Delivery is improved by providing a system which creates particlesfor systemic delivery wherein the particles are in the range of about0.5 to about 12.0 microns, preferably 0.5 to 6 microns and morepreferably 0.5 to about 3 microns.

(4) It is desirable to have obtained a concentration of the drug in thecarrier in the range of from about 0.01 to about 12.50 preferably 0.1 to10%. By maintaining the concentration of drug to carrier in this rangeit is possible to create particles which are somewhat larger than wouldbe desirable for delivery but to reduce those particles in size byevaporation of carrier.

(5) Air drawn into the flow path of the aerosolized particles can beheated by adding energy to each 10 μl of formulation in an amount ofabout 20 Joules to 100 Joules, more preferably 20 Joules to 50 Joules.The heated air aids in reducing the effect of humidity and evaporatescarrier away from the particles thereby providing smaller particles forinhalation.

(6) Air is added to the aerosolized formulation by the patient drawingair into the aerosolized mist in an amount of about 50 milliliters to 2liters per 10 microliters of aerosol formulation.

(7) Vibration may be created on the porous membrane in an amount 575 to32,000, preferably 1,000 to 17,000 and more preferably 2,000 to 4,000kilohertz.

(8) The pore size of the membrane is regulated within a range of 0.25 toabout 6.0 microns, preferably 0.5 to 3 microns and more preferably 1 to2 microns. This size refers to the diameter of the pore through whichthe formulation exits the membrane. The diameter of the opening intowhich the formulation flows may be 2 to 20 times that size in diameterthereby providing a conical configuration.

(9) The viscosity of the formulation and the membrane porosity affectthe amount of pressure which needs to be applied to force theformulation through the pores over a given period of time and theviscosity should be within the range of 25% to 1,000% the viscosity ofwater.

(10) The extrusion pressure is regulated within a range of 50 to 600 psimore preferably 100 to 500 psi. Lower pressures may be obtained by usingthe conical configuration for the pore size.

(11) The microprocessor should also be provided information regardingthe ambient temperature and atmospheric pressure. The temperature ispreferably close to room temperature i.e., within a range of 15° C. to30° C. An atmospheric pressure is generally 1 atmosphere or slightlylower at higher altitudes, e.g., about 75% of 1 atmosphere.

(12) To provide for consistency in dosing the ratio of the carrier todrug should be maintained constant and more highly concentrated insulinformulation are more desirable.

(13) A desiccator is preferably used to remove water vapor from airdrawn into the flow path by the patient.

(14) The pores are preferably placed in the porous membrane in anelongated oval or elongated rectangular configuration. By configuringthe pores in this manner and drawing air perpendicularly over thenarrower dimension of the configuration it is possible to reduce theamount of collisions between particles and thereby avoid particlescollision resulting in accumulation.

(15) The thickness of the membrane is preferably regulated in the rangeof 5 to 200 microns or more preferably 10 to 50 microns. Thinnermembranes are useful in that less pressure is required to forceformulation through the membrane. The membrane has a tensile strength of5,000 to 20,000, preferably 8,000 to 16,000 and more preferably 14,000to 16,000 psi.

(16) The membrane is configured so as to have a convex configurationwhich protrudes into faster moving air created by the patient'sinhalation or is designed to be flexible so that it will assume a convexconfiguration when formulation is forced through the membrane.

(17) After the microprocessor is provided information with respect toabove parameters or measurements a drug release point is chosen themicroprocessor will continually return to substantially the same firingpoint at each drug delivery so as to obtain repeatability of dosing.

After drug has been delivered it is possible to discontinue any readingswith respect to flow and/or volume. However, it is preferable tocontinue readings with respect to both criteria after drug has beenreleased. By continuing the readings the adequacy of this patient'sparticular drug delivery maneuver can be determined. All of the eventsare recorded by the microprocessor. The recorded information can beprovided to the caregiver for analysis. For example, the caregiver candetermine if the patient correctly carried out the inhalation maneuverin order to correctly delivery drug and can determine if the patient'sinhalation profile is effected by the drug.

Monitoring Diabetic Control

All methods of treating diabetes involve measuring glucose levels insome manner. Such measurements are necessary in order to titrate properdosing and avoid the over-administration of insulin which can result infatal hypoglycemia. Measurements of urine glucose alone are insufficientto assess diabetic control and bring mean plasma glucose values into anear normal range since the urine will be free of glucose when theplasma concentration is relatively normal. For this reason, "homeglucose monitoring" is used in those patients treated by continuoussubcutaneous insulin infusion (CSII) or multiple subcutaneous injection(MSI) techniques. Such monitoring requires capillary blood which can beobtained in a substantially painless manner using a smallspring-triggered device referred to as Autolet™ produced by UlstrScientific Incorporated which device is equipped with small disposablelancelets. The amount of glucose is analyzed using chemicallyimpregnated strips which are read in a commercially availablereflectance meter. One commercially available strip is referred to asChemstrip bG (produced by Bio-Dynamics). The Chemstrip Bg can providesatisfactory values by visual inspection utilizing a dual-color scale,thus eliminating the need for a reflectance meter. Frequent measurementof the plasma glucose (a fairly standard program utilizes seven or eightassays over a 24-hour period) allows a reasonable assessment of meanplasma glucose levels during the day and guides adjustment of insulindosage.

The methodology of the present invention is preferably utilized incombination with a closely controlled means of monitoring serum glucoselevels. More specifically, the drug delivery device of the invention isused to administer doses of insulin via the intrapulmonary route. Thedoses may be administered in somewhat smaller amounts than are generallyadministered by injection. The amount of insulin administered can bereadily adjusted in that smaller amounts are generally administeredusing the intrapulmonary delivery methodology of the present invention.

After an aerosolized dose of insulin has been produced and inhaled intothe patient's lungs the inhale-exhale maneuver can be performed at anytime. Performing the maneuver provides advantages in that it increasesthe rate at which the insulin enters the circulatory system and therebymakes it possible to more accurately control the amount of additionalinsulin the patient might need in order to properly adjust the glucoselevel. If the maneuver is not performed a greater amount of time mustpass until the patient is sure that sufficient insulin has not alreadybeen absorbed. Regardless of the manner by which the insulin isadministered i.e., by injection or inhalation there is some lag timebetween the administration of a dose of insulin and its effect on theserum glucose level. Thus, regardless of the means of administration andeven when the inhale-exhale maneuver is performed some time must beallowed to pass for the glucose level to decrease prior to theadministration of additional insulin in order to avoid overdosing. Theuse of the inhale-exhale maneuver decreases the "lag" time which isalready decreased due to intrapulmonary administration as compared tosubcutaneous injections. Further, as indicated above, the microprocessorcan be programmed to prevent overdoses.

During the day, as insulin is administered, serum glucose levels arefrequently monitored. The amount of insulin administered can be dosedbased on the monitored serum glucose levels, i.e., as glucose levelsincrease, the amount of insulin can be increased, and as glucose levelsare seen to decrease, the dosing of insulin can be decreased.

Based on the information disclosed herein in combination with what isknown about insulin dosing and serum glucose levels, computer readableprograms can be readily developed which can be used in connection withthe insulin delivery device of the present invention. More specifically,the microprocessor can be programmed so as to deliver precise doses ofinsulin which correspond to the particular needs of the patient based onserum glucose monitoring information which is supplied to themicroprocessor of the device of the invention. Further, the dosinginformation contained within the microprocessor of the device of theinvention can be fed to a separate computer and/or serum glucosemonitoring device (preferably portable) in order to calculate the besttreatment and dosing schedule for the particular patient.

Insulin Containing Formulations

A variety of different insulin containing formulations can be used inconnection with the present invention. The active ingredient within suchformulations is insulin which is preferably recombinantly produced humaninsulin but, as indicated above, may include insulin extracted fromanimal sources. Further, the insulin may be an insulin analog which isan analog of human insulin which has been recombinantly produced.Although the insulin and/or analog is generally present by itself as thesole active ingredient, the insulin may be present with an additionalactive ingredient such as a sulfonylurea. However, such sulfonylureasare generally administered separately in order to more closely controldosing and serum glucose levels.

The present invention provides a great deal of flexibility with respectto the types of insulin to be administered. For example, a container caninclude insulin by itself or insulin in combination with an insulinanalog of any type or combinations of different insulin analogs.Further, a package can be created wherein individual containers includedifferent formulations wherein the formulations are designed to achievea particular effect e.g., fast acting insulin or quick absorbinginsulin. The patient along with the care giver and careful monitoringcan determine the preferred insulin dosing protocol to be followed forthe particular patient.

Regardless of the active ingredient, there are several basic types ofinsulin formulations which can be used in connection with the presentinvention. All of the formulations include insulin, preferably with apharmaceutically acceptable carrier suitable for intrapulmonaryadministration.

The insulin may be provided as a dry powder by itself, and in accordancewith another formulation, the insulin or active ingredient is providedin a solution formulation. The dry powder could be directly inhaled byallowing inhalation only at the same measured inspiratory flow rate andinspiratory volume for each delivery. However, the powder is preferablydissolved in an aqueous solvent to create a solution which is movedthrough a porous membrane to create an aerosol for inhalation.

Any formulation which makes it possible to produce aerosolized forms ofinsulin which can be inhaled and delivered to a patient via theintrapulmonary route can be used in connection with the presentinvention. Specific information regarding formulations (which can beused in connection with aerosolized delivery devices) are describedwithin Remington's Pharmaceutical Sciences, A. R. Gennaro editor (latestedition) Mack Publishing Company. Regarding insulin formulations, it isalso useful to note Sciarra et al. Journal of Pharmaceutical Sciences,Vol. 65, No. 4, 1976!.

The insulin is preferably included in a solution such as the type ofsolution which is made commercially available for injection and/or othersolutions which are more acceptable for intrapulmonary delivery. Whenpreparing preferred formulations of the invention which provide for theinsulin, excipient and solvent, any pharmaceutically acceptableexcipient may be used provided it is not toxic in the respiratory tract.

Formulations include insulin dry powder by itself and/or with anexcipient. When such a formulation is used, it may be used incombination with a gas propellant which gas propellant is released overa predetermined amount of dried powder which is forced into the air andinhaled by the patient. It is also possible to design the device so thata predetermined amount of dry powder is placed behind a gate. The gateis opened in the same manner as the valve is released so that the sameinspiratory flow rate and inspiratory volume is repeatedly obtained.Thereafter, the dry powder is inhaled by the patient and the insulin isdelivered. When a solution is used the device of FIG. 4 is used tocreate an aerosolized form of the solution which can be inhaled by thepatient.

Formulations of the invention can include liposomes containing insulinin combination with an amount of alveolar surfactant protein effectiveto enhance the transport of the liposomes across the pulmonary surfaceand into the circulatory system of the patient. Such liposomes andformulations containing such are disclosed within U.S. Pat. No.5,006,343, issued Apr. 9, 1991, which is incorporated herein byreference to disclose liposomes and formulations of liposomes used inintrapulmonary delivery. The formulations and methodology disclosed inU.S. Pat. No. 5,006,343 can be adapted for the application of insulinand included within the delivery device of the present invention inorder to provide for effective treatments of diabetic patients.

The terms "insulin" and "insulin analog" have been defined above. Withrespect to both terms, applicant points out that a variety of commercialinsulin formulations are available. Rapidly acting preparations arealways indicated in diabetic emergencies and in CSII and MSI programs.Intermediate preparations are used conventional and MSI regimens. It isnot possible to delineate precisely the biologic responses to thevarious preparations because peak effects and duration vary from patientto patient and depend not only on route of administration but on dose.The various insulins are available as rapid (regular, semilente),intermediate (NPH, lente, globin), and long-acing (PZI, ultralente)preparations, although not all manufacturers offer all varieties. Lenteand NPH insulin are used in most conventional therapy and are roughlyequivalent in biologic effects, although lente appears to be slightlymore immunogenic and to mix less well with regular insulin than doesNPH.

Preferred Flow Rates/Volumes

FIG. 9 is a two-dimensional graph wherein the inspiratory flow rate isplotted against the inspiratory volume. To determine a drug releasepoint the patient's inspiratory flow rate and inspiratory volume may besimultaneously and separately determined, e.g., measured. Themeasurement is taken and the information obtained from the measurementprovided to a microprocessor which microprocessor is programmed torelease drug (1) at the same point relative to inspiratory flow andinspiratory volume at each release of drug and (2) to select that pointwithin prescribed parameters of inspiratory flow rates and inspiratoryvolumes. In the particular results plotted in FIG. 9 the microprocessorwas programmed to release drug in four general areas with respect to theinspiratory flow rate and inspiratory volume parameters. This resultedin data points being plotted in four general areas on thetwo-dimensional graph of FIG. 9. The four areas are labeled A, B, C andD. In area A (showing solid triangles), the drug was released when thepatient's inspiratory flow rate was "slow to medium" (0.10 to 2.0 litersper sec) with an "early" inspiratory volume of 0.15 to 0.8 liters. Inarea B (showing open triangles), the drug was released at a "slow"inspiratory rate/0.10 to 1.0 liters/sec) and a "late" volume (1.6 to 2.8liters). In area C (showing solid diamonds), the drug was released at a"fast" inspiratory flow rate (3.5 to 4.5 liters/sec) and a "late"volume. In area D (showing solid circles), the drug was released at a"fast inspiratory flow rate and an "early" inspiratory volume.

The results shown in FIG. 9 were obtained while administering aradioactively labeled drug to a human. After the administration of thedrug it was possible to determine not only the amount of drug, but thepattern of drug deposited within the lungs of the patient. Using thisinformation two conclusions were reached. Firstly, it was determinedthat it is important to simultaneously and separately consider (in realtime) both inspiratory flow rate and inspiratory volume when determiningthe point for drug release for intrapulmonary drug delivery. Changes ineither parameter can greatly effect the amount of drug deposited. Thus,when treating a patient the drug should be released at approximately(±10%, preferably ±5% and most preferable as close as possible to thefirst release point) the same inspiratory flow rate and inspiratoryvolume each time--going back to the same point each time for the samepatient ensures repeatable dosing. In practice the tighter the point isdefined the greater the repeatability of dosing. However, if the pointis defined to precisely it can be difficult for the patient to obtainthat rate/volume point again. Thus, some degree of tolerance isgenerally applied. Secondly, it was found that within particular rangeswith respect to inspiratory flow rate and inspiratory volume it waspossible to obtain a consistently high percentage amount of drugdeposited in the lung. Such results are shown graphically within thethree dimensional graph as shown in FIG. 10.

The third dimension as shown in FIG. 10 (the height of the four columns)indicates the percentage amount of drug deposited based on the totalamount of drug released to the patient. The area labeled A clearlyshowed the highest percentage of drug delivered to the patient based onthe amount of drug released. Using this information it was possible tocalculate a specific area regarding inspiratory flow rate andinspiratory volume at which it is possible to obtain not only a highdegree of repeatability in dosing, but obtain a higher percentage ofdrug being delivered based on the percentage of drug released.Specifically, it was determined that the drug should be released withininspiratory flow rate range of 0.10 to 2.0 liters per second and at aninspiratory volume in the range of about 0.15 to about 0.80 liters. Thisrange is shown by the rectangularly shaped column of FIG. 11.

In that intrapulmonary drug delivery systems often provide for erraticdosing it is important to provide a method which allows for consistent,repeatable dosing. This is obtained by simultaneously and separatelyconsidering both inspiratory flow rate and inspiratory volume in orderto define a point by its abscissa and ordinate for optimal delivery tothe lung. If both measurements are separately considered the drug can bereleased anywhere along the abscissa and ordinate scales shown in FIG.9. Once a point is selected (such as by randomly selecting a point inbox A of the graph of FIG. 9) that selected point (with the samecoordinants) is used again and again by a given patient to obtainrepeatable dosing. If only one parameter is measured (abscissa orordinate) and drug is released based on that parameter the drug releasepoint is defined by a line on the graph of FIG. 9. When drug is releasedagain the release can be at any point on that line. For example, theinspiratory flow rate (measured horizontally on the abscissa) might bedefined by a point. However, the inspiratory volume (which was notmeasured and/or considered) would be defined only by a vertical line.Thus, subsequent releases would be at different volumes along thatvertical line and the dosing would not be consistent. By measuring bothinspiratory flow rate on the abscissa and inspiratory volume on theordinant the coordinants will mark a point for drug release. That pointcan be found again and again to obtain repeatability in dosing. The samepoint should be selected each time as closely as possible and within amargin of errors of ±10% with respect to each criteria. The margin forerror can be increased and still maintain acceptable levels ofrepeatable dosing--but the error should keep the drug release pointinside the box A of FIG. 9.

By examining delivery of drug associated with the data points plotted inFIG. 9, it is possible to determine a preferred and particularlypreferred and most preferred range as per FIGS. 11, 12 and 13. Thepreferred range of FIG. 11 shows drug released at a volume of 0.15 to0.8 liters and rate of 0.10 to 2.0 liters/second. The particularlypreferred range plotted in FIG. 12 indicates that the inspiratory flowshould be within the range of 0.2 to about 1.8 liters per second with aninspiratory volume in the range of 0.15 to about 0.4 liters. The mostpreferred range (FIG. 13) is from about 0.15 to about 1.8 liters persecond for the inspiratory flow rate and about 0.15 to about 0.25 litersfor the inspiratory volume. Thus, preferred delivery can be obtained by(1) repeatedly delivering aerosolized formulation to a patient at thesame simultaneously and separately measured inspiratory flow rate andinspiratory volume and (2) releasing drug to the patient withinspecified therapeutically effective ranges as shown within FIGS. 11, 12and 13. The invention involves releasing drug (after measuring) insidethe ranges as per FIGS. 11, 12 or 13. Thus, the release could begininside or outside the range. Preferably the drug release begins insidethe range and more preferable begins and ends inside the ranges of FIGS.11, 12 or 13.

The methodology of the invention may be carried out using a portable,hand-held, battery-powered device which uses a microprocessor componentas disclosed in U.S. Pat. Nos. 5,404,871, issued Apr. 11, 1995 and5,450,336, issued Sep. 12, 1995 both of which are incorporated herein byreference. In accordance with another system the methodology of theinvention could be carried out using the device, dosage units and systemdisclosed in U.S. Ser. No. 94/05825 with modifications as describedherein. Insulin (which is preferably recombinant insulin) is included inan aqueous formulation which is aerosolized-by moving the formulationthrough a flexible porous membrane. Alternatively, the methodology ofthe invention could be carried out using a mechanical (non-electronic)device. Those skilled in the art recognized that various components canbe mechanical set to actuate at a given inspiratory flow rate (e.g. aspring biased valve) and at a given volume (e.g. a spinable flywheelwhich rotates a given amount per a given volume). The components of suchdevices could be set to allow drug release inside the parameters ofFIGS. 11, 12 or 13.

The insulin which is released to the patient may be in a variety ofdifferent forms. For example, the insulin may be an aqueous solution ofdrug, i.e., drug dissolved in water and formed into small particles tocreate an aerosol which is delivered to the patient. Alternatively, thedrug may be in a solution or a suspension wherein a low-boiling pointpropellant is used as a carrier fluid. In yet, another embodiment theinsulin may be in the form of a dry powder which is intermixed with anairflow in order to provide for delivery of drug to the patient.Regardless of the type of drug or the form of the drug formulation, itis preferable to create drug particles having a size in the range ofabout 0.5 to 12 microns. By creating drug particles which have arelatively narrow range of size, it is possible to further increase theefficiency of the drug delivery system and improve the repeatability ofthe dosing. Thus, it is preferable that the particles not only have asize in the range of 0.5 to 12 microns but that the mean particle sizebe within a narrow range so that 80% or more of the particles beingdelivered to a patient have a particle diameter which is within ±20% ofthe average particle size, preferably ±10% and more preferably ±5% ofthe average particle size.

The velocity at which the aerosolized drug is released to the patient isalso important in terms of obtaining a high degree of repeatability indosing and providing for a high percentage of drug being delivered tothe patient's lungs. Most preferably, the drug is released from acontainer in a direction which is normal to the patient's airflow.Accordingly, the drug in a container 1 as shown in FIG. 3 may bereleased directly upward so that its flow is at a 9° angle with respectto the patient's inspiratory flow which is directly horizontal. Afterbeing released, the drug velocity decreases and the drug particlesremain suspended for a sufficient period of time to allow the patient'sinspiration to draw the drug into the patient's lungs. The velocity ofdrug released in the direction from the drug release point to thepatient may match the patient's inspiratory flow rate but is preferablyslower that the patient's inspiratory flow rate and is most preferablyabout zero. The velocity may be slightly negative, i.e., in a directionaway from the patient. The velocity may range from -2.0 liters/sec to2.0 liters/sec and is preferably zero. It is not desirable to projectthe drug toward the patient at a rate above the speed of the patient'sbreath as such may result in drug being deposited on the back of thepatient's throat. Thus, the drug release speed should be equal to orless than the breath speed. The actual speed of release can varydepending on factors such as the particle size, the particle compositionand the distance between the point of release and the patient. Thevelocity is preferably such that the particles will (due to airresistance) slow to zero velocity after traveling a distance of about 2centimeters or less. In general, the shorter the distance required toslow the particles to zero velocity the better.

An aerosol may be created by forcing drug through pores of a membranewhich pores have a size in the range of about 0.25 to 6 micronspreferably 0.5 to 3.0 microns. When the pores have this size theparticles which escape through the pores to create the aerosol will havea diameter about twice the diameter of the pore opening from which theformulation exists. However, the particle size can be substantiallyreduced by adding heat to the air around the particles and causeevaporation of carrier. Drug particles may be released with an air flowintended to keep the particles within this size range. The creation ofsmall particles may be facilitated by the use of the vibration devicewhich provides a vibration frequency in the range of about 800 to about4000 kilohertz. Those skilled in the art will recognize that someadjustments can be made in the parameters such as the size of the poresfrom which drug is released, vibration frequency and amplitude,pressure, and other parameters based on the concentration, density,viscosity and surface tension of the formulation keeping in mind thatthe object is to provide aerosolized particles having a diameter in therange of about 0.5 to 12 microns.

The drug formulation may be a low viscosity liquid formulation. Theviscosity of the drug by itself or in combination with a carrier is notof particular importance except to note that the formulation must havecharacteristics such that it can be forced out of openings of theflexible or convex membrane to form an aerosol, e.g., using 20 to 400psi to form an aerosol preferably having a particle size in the range ofabout 0.5 to 6.0 microns.

Drug may be stored in and/or released from a container of any desiredsize. In most cases the size of the container is not directly related tothe amount of drug being delivered in that most formulations includerelatively large amounts of excipient material e.g. water or a salinesolution. Accordingly, a given size container could include a wide rangeof different doses by varying drug concentration.

Drug containers may include indices which may be electronic and may beconnected to a power source such as a battery. When the indices are inthe form of visually perceivable numbers, letters or any type of symbolcapable of conveying information to the patient. Alternatively, theindices may be connected to a power source such as a battery when theindices are in the form of magnetically, optically or electronicallyrecorded information which can be read by a drug dispensing device whichin turn provides visual or audio information to the user. The indicescan be designed for any desired purpose but in general provides specificinformation relating to the day and/or time which the drug within acontainer should be administered to the patient. Such indices mayrecord, store and transfer information to a drug dispensing deviceregarding the number of doses remaining in the container. The containersmay include labeling which can be in any format and could include daysof the month or other symbols or numbers in any variation or language.

In addition to disclosing specific information regarding the day andtime for drug delivery the indices could provide more detailedinformation such as the amount of insulin dispensed from each containerwhich might be particularly useful if the containers included differentamounts of insulin. Further, magnetic, optical and/or electronic indicescould have new information recorded onto them which information could beplaced there by the drug dispensing device. For example, a magneticrecording means could receive information from the drug dispensingdevice indicating the precise time which the insulin was actuallyadministered to the patient. In addition to recording the time ofdelivery the device could monitor the expected efficacy of the deliverybased on factors such as the inspiratory flow rate which occurredfollowing the initial release of insulin. The information recorded couldthen be read by a separate device, interpreted by the care-giver andused to determine the usefulness of the present treatment methodology.For example, if the glucose levels of the patient did not appear to beresponding well but the recorded information indicating that the patienthad taken the drug at the wrong time or that the patient hadmisdelivered drug by changing inspiratory flow rate after initialrelease it might be determined that further education in patient use ofthe device was needed but that the present dosing methodology might wellbe useful. However, if the recordings indicated that the patient haddelivered the aerosolized insulin using the proper techniques and stillnot obtained the correct results (e.g. acceptable glucose levels)another dosing methodology might be recommended. The method of treatingDiabetes Mellitus may be carried out using a hand-held, portable devicecomprised of (a) a device for holding a disposable package comprised ofat least one but preferably a number of drug containers, (b) apropellant or a mechanical mechanism for moving the contents of acontainer through a porous membrane (c) a monitor for analyzing theinspiratory flow, rate and volume of a patient, and (d) a switch forautomatically releasing or firing the mechanical means after theinspiratory flow and/or volume reaches a threshold level. The device mayalso include a transport mechanism to move the package from onecontainer to the next with each container and its porous membrane beingdisposed of after use. The entire device is self-contained, light weight(less than 1 kg preferably less than 0.5 kg loaded) and portable.

The device may include a mouth piece at the end of the flow path, andthe patient inhales from the mouth piece which causes an inspiratoryflow to be measured within the flow path which path may be in anon-linear flow-pressure relationship. This inspiratory flow causes anair flow transducer to generate a signal. This signal is conveyed to amicroprocessor which is able to convert, continuously, the signal fromthe transducer in the inspiratory flow path to a flow rate in liters perminute. The microprocessor can further integrate this continuous airflow rate signal into a representation of cumulative inspiratory volume.At an appropriate point in the inspiratory cycle, the microprocessor cansend a signal to an actuation means (and/or a vibration device below theresonance cavity). When the actuation means is signaled, it causes themechanical means (by pressure and/or vibration) to move drug from acontainer on the package into the inspiratory flow path of the deviceand ultimately into the patient's lungs. After being released, the drugand carrier will pass through a porous membrane, which can be vibratedto aerosolize the formulation and thereafter the lungs of the patient.

It is important to note that the firing threshold of the device is notbased on a single criterion such as the rate of air flow through thedevice or a specific time after the patient begins inhalation. Thefiring threshold is based on repeating the firing at the same flow rateand volume as per FIGS. 9-13. This means that the microprocessorcontrolling the device takes into consideration the instantaneous airflow rate as well as the cumulative inspiratory flow volume. Both aresimultaneously considered together in order to determine the optimalpoint in the patient's inspiratory cycle most preferable in terms of (1)reproducibly delivering the same amount of drug to the patient with eachrelease of drug by releasing drug at the same point each time andmaximizing the amount of drug delivered as a percentage of the totalamount of drug released by releasing with the parameters describedherein.

The device preferably includes a means for recording a characterizationof the inspiratory flow profile for the patient which is possible byincluding a microprocessor in combination with a read/write memory meansand a flow measurement transducer. By using such devices, it is possibleto change the firing threshold at any time in response to an analysis ofthe patient's inspiratory flow profile, and it is also possible torecord drug dosing events over time. In a particularly preferredembodiment the characterization of the inspiratory flow can be recordedonto a recording means on the disposable package.

The details of a drug delivery device which includes a microprocessorand pressure transducer of the type which may be used in connection withthe present invention are described and disclosed within U.S. Pat. Nos.5,404,871, issued Apr. 11, 1995 and 5,450,336, issued Sep. 12, 1995incorporated in their entirety herein by reference, and specificallyincorporated in order to describe and disclose the microprocessor andprogram technology used therewith. The pre-programmed information iscontained within a nonvolatile memory which can be modified via anexternal device. In another embodiment, this pre-programmed informationis contained within a "read only" memory which can be unplugged from thedevice and replaced with another memory unit containing differentprogramming information. In yet another embodiment, a microprocessor,containing read only memory which in turn contains the pre-programmedinformation, is plugged into the device. For each of these embodiments,changing the programming of the memory device readable by amicroprocessor will radically change the behavior of the device bycausing the microprocessor to be programmed in a different manner. Thisis done to accommodate different insulin formulation and for differenttypes of treatment, e.g., patients with different types of diabetes.

In a preferred embodiment of the methodology of the invention severaldifferent criteria are considered. (1) The inspiratory flow rate andinspiratory volume are simultaneously and separately measured to insurerepeatability. (2) The drug is released inside the parameters of FIGS.11, 12 or 13 with FIG. 13 parameters being most preferred. (3) Theparticle size of the released drug is in the range of 0.5 to 12 micronsand 80% or more and the particles have the same size as the averageparticle size ±10% in size. (4) The drug particles are released at avelocity which is obtained at a flow rate in the range of greater than-2.0 liters/sec. and less than 2.0 liters/sec. As indicated early theactual velocity can vary based on a number of factors. The releasevelocity should be determined so that the particles are at or are slowedto zero velocity after traveling about 0.5 to 2 cm from the releasepoint in the absence of patient inhalation. The speed being measuredfrom the drug release point in a direction toward the back of the throatof the patient from the drug release point.

After dosing a patient with insulin it is desirable to measure glucose(invasively or non-invasively) and make adjustments as needed to obtainthe desired glucose level. In accordance with all methods the patientdoes not push a button to release drug. The drug is releasedautomatically by signals from the microprocessor using measurementsobtained.

The doses administered are based on an assumption that wheninterpulmonary delivery methodology is used the efficiency of thedelivery is at a known percent amount, e.g., 20% to 50% or moreapproximately and adjustments in the amount released in order to takeinto account the efficiency of the device. The differential between theamount of insulin actually released from the device and the amountactually delivered to the patient varies due to a number of factors. Ingeneral, devices used with the present invention can have an efficiencyas low as 10% and as high as 50% or more meaning that as little as 10%of the released insulin may actually reach the circulatory system of thepatient and as much as 50% or more might be delivered. The efficiency ofthe delivery will vary somewhat from patient to patient and must betaken into account when programming the device for the release ofinsulin. In general, a conventional metered (propellant-driven) doseinhaling device is about 10% efficient.

One of the important features and advantages of the present invention isthat the microprocessor can be programmed to take a variety of differentcriteria into consideration with respect to dosing times. Specifically,the microprocessor can be programmed so as to include a minimum timeinterval between doses i.e. after a given delivery another dose cannotbe delivered until a given period of time has passed. Secondly, thetiming of the device can be programmed so that it is not possible toexceed the administration of a set maximum amount of insulin within agiven time. For example, the device could be programmed to preventdispersing more than 5 units of insulin within one hour. Moreimportantly, the device can be programmed to take both criteria intoconsideration. Thus, the device can be programmed to include a minimumtime interval between doses and a maximum amount of insulin to bereleased within a given time period. For example, the microprocessorcould be programmed to allow the release of a maximum of 5 units ofinsulin during an hour which could only be released in amounts of 1 unitwith each release being separated by a minimum of five minutes.

Additional information regarding dosing with insulin via injection canbe found within Harrison's--Principles of Internal Medicine (most recentedition) published by McGraw Hill Book Company, New York, incorporatedherein by reference to disclose conventional information regardingdosing insulin via injection.

Another feature of the device is that it may be programmed to notrelease drug if it does not receive a signal transmitted to it by atransmitter worn by the intended user. Such a system improves thesecurity of the device and prevents misuse by unauthorized users such aschildren.

The microprocessor of the invention can be connected to external devicespermitting external information to be transferred into themicroprocessor of the invention and stored within the non-volatileread/write memory available to the microprocessor. The microprocessor ofthe invention can then change its drug delivery behavior based on thisinformation transferred from external devices such as a glucosemonitoring device. All of the features of the invention are provided ina portable, programmable, battery-powered, hand-held device for patientuse which has a size which compares favorably with existing metered doseinhaler devices.

Different mechanisms will be necessary in order to deliver differentformulations, such as a dry powder without any propellant. A devicecould be readily designed so as to provide for the mechanical movementof a predetermined amount of dry powder to a given area. The dry powderwould be concealed by a gate, which gate would be opened in the samemanner described above, i.e., it would be opened when a predeterminedflow rate level and cumulative volume have been achieved based on anearlier monitoring event. Patient inhalation or other source of energysuch as from compressed gas or a mechanical device would then cause thedry powder to form a dry dust cloud and be inhaled.

In addition to monitoring glucose levels in order to determine properinsulin dosing, the microprocessor of the present invention isprogrammed so as to allow for monitoring and recording data from theinspiratory flow monitor without delivering drug. This is done in orderto characterize the patient's inspiratory flow profile in a given numberof monitoring events, which monitoring events preferably occur prior todosing events. After carrying out a monitoring event, the preferredpoint within the inspiratory cycle for drug delivery can be calculated.This calculated point is a function of measured inspiratory flow rate aswell as calculated cumulative inspiratory flow volume. This informationis stored and used to allow activation of the valve when the inhalationcycle is repeated during the dosing event. Those skilled in the art willalso readily recognize that different mechanisms will be necessary inorder to deliver different formulations, such as a dry powder withoutany propellant. A device could be readily designed so as to provide forthe mechanical movement of a predetermined amount of dry powder to agiven area. The dry powder would be concealed by a gate, which gatewould be opened in the same manner described above, i.e., it would beopened when a predetermined flow rate level and cumulative volume havebeen achieved based on an earlier monitoring event. Patient inhalationwould then cause the dry powder to form a dry dust cloud and be inhaled.Dry powder can also be aerosolized by compressed gas, and a solution canbe aerosolized by a compressed gas released in a similar manner and theninhaled.

Dual Compartment Container

The dual compartment container 70 of FIG. 14 includes a first container71 and a second container 72. The containers 71 and 72 are in fluidconnection with each other but the fluid connection is interrupted by amembrane 73 which membrane can be ruptured by the application ofpressure (preferably in an amount of about 50 psi or less). A devicesuch as the component 74 forces against the bottom of the container 72and forces the contents 75 (which is liquid) against the membrane 73which is then ruptured. The liquid 75 then enters the container 71 andmixes with the dry powder insulin 76 present with the container 71. Thecontainer 71 may include mixing components 77 and 78. These componentsmay be vibrating devices, ultrasonic devices or other suitablemechanisms allowing for the mixing of the liquid with the dry insulin.When the mixing is completed the component 79 is forced against thecontainer 71 forcing the insulin formulation present therein into thechamber 80. Once the formulation is in the chamber 80 it is there underpressure and can be moved through the flexible membrane 81 by theapplication of that pressure and/or by the use of a vibrating device 82.The formulation is moved through the membrane 81 only after removal ofthe cover sheet 83.

The membrane 81 may be permanently convexed or may be flexible andconvex outward when the formulation is forced through the membrane andwill operate as per the container described in FIGS. 1-4 above. Themembrane 81 includes pores having a diameter in the range of about 0.25micron to about 6 microns and a pore density in the range of 1×10⁴ toabout 1×10⁸ pores per square centimeter. The porous membrane 81 ispreferably comprised of a material having a density in the range ofabout 0.25 to 3.0 mg/cm², more preferably about 1.7 mg/cm² and athickness of about 2 to about 20 microns, more preferably 8 to 12microns. The liquid 75 present in the container 72 is preferably capableof dissolving the insulin. The insulin powder 76 is preferablycompletely dissolved within the container 71 prior to being forced intothe chamber 80. Dissolving the insulin makes it easier to move theinsulin through the pores of the membrane 81 and create a fine mistaerosol. Keeping the dried insulin apart from the liquid makes itpossible to maintain a longer shelf life.

The instant invention is shown herein in what is considered to be themost practical and preferred embodiments. It is recognized, however,that departures may be made therefrom which are within the scope of theinvention and that obvious modifications will occur to one skilled inthe art upon reading this disclosure.

We claim:
 1. A method of enhancing the rate at which an inhaled drugmigrates into a patient's circulatory system, comprising:aerosolizing aformulation comprised of a monomeric insulin; inhaling the aerosolizedformulation into lungs of a patient and allowing particles of themonomeric insulin to deposit on lung tissue.
 2. The method of claim 1,further comprising:inhaling maximally followed by exhaling the forcedvital capacity of the lungs; wherein the inhaling maximally and exhalingthe forced vital capacity are measured.
 3. The method of claim 2,wherein the measuring is carried out electronically and a first signalis sent after the inhaling reaches a desired point and a second signalis sent after the exhaling reaches a desired point.
 4. The method ofclaim 1, wherein the formulation is a liquid formulation comprised of apharmaceutically acceptable carrier and insulin lispro.
 5. A method ofimproving the bioavailability of insulin delivered via the lung,comprising:aerosolizing a formulation of an insulin analog which analograpidly disassociates into monomeric form; inhaling the aerosolizedformulation of the insulin analog into the lungs in a manner whichallows the particles of the insulin analog to deposit on the lungtissue.
 6. The method of claim 5, wherein the inhaled insulin analog isinsulin lispro which rapidly disassociates in a monomeric form producinga relative bioavailability greater than twice that seen after theinhalation of a similar amount of recombinant human insulin.
 7. A methodof reducing sequestration of drug on lung tissue,comprising:aerosolizing a formulation comprised of a monomeric insulin;inhaling the aerosolized formulation into lungs of a patient andallowing particles of the monomeric insulin to deposit on lung tissue.8. The method of claim 7, wherein the monomeric insulin is insulinlispro.
 9. The method of claim 7, further comprising:inhaling maximallyfollowed by exhaling the forced vital capacity of the lungs.
 10. Themethod of claim 9, further comprising:electronically measuring theinhaling and exhaling.
 11. The method of claim 10, furthercomprising:sending a first signal after the inhaling reaches a desiredpoint; and sending a second signal after the exhaling reaches a desiredpoint.
 12. The method of claim 1, wherein the insulin is insulin lispro.13. The method of claim 1, further comprising:inhaling maximallyfollowed by exhaling the forced vital capacity of the lungs.
 14. Themethod of claim 13, further comprising:electronically measuring theinhaling and exhaling.
 15. A method of reproducibly effecting a serumglucose level, comprising:aerosolizing a formulation comprisingmonomeric insulin; administering the aerosolized formulation.
 16. Themethod of claim 15, further comprising:repeatedly administering theaerosolized formulation at substantially the same inspiratory flow rateand inspiratory volume at each administration.
 17. The method of claim15, wherein the monomeric insulin is insulin lispro.
 18. The method ofclaim 15, further comprising:monitoring inspiratory flow rate andinspiratory volume; and automatically releasing aerosolized formulationbased on a monitored rate and volume.
 19. The method of claim 15,further comprising:inhaling maximally followed by exhaling the forcedvital capacity of the lungs.
 20. The method of claim 19, furthercomprising:measuring the inhaling maximally and exhaling the forcedvital capacity.
 21. The method of claim 20, wherein the measuring iscarried out electronically and a first signal is sent after the inhalingreaches a desired point and a second signal is sent after the exhalingreaches a desired point.